Browsing by Subject "NEURONS"

Sort by: Order: Results:

Now showing items 1-20 of 60
  • Romano, Roberta; Rivellini, Cristina; De Luca, Maria; Tonlorenzi, Rossana; Beli, Raffaella; Manganelli, Fiore; Nolano, Maria; Santoro, Lucio; Eskelinen, Eeva-Liisa; Previtali, Stefano C.; Bucci, Cecilia (2021)
    The small GTPase RAB7A regulates late stages of the endocytic pathway and plays specific roles in neurons, controlling neurotrophins trafficking and signaling, neurite outgrowth and neuronal migration. Mutations in the RAB7A gene cause the autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) disease, an axonal peripheral neuropathy. As several neurodegenerative diseases are caused by alterations of endocytosis, we investigated whether CMT2B-causing mutations correlate with changes in this process. To this purpose, we studied the endocytic pathway in skin fibroblasts from healthy and CMT2B individuals. We found higher expression of late endocytic proteins in CMT2B cells compared to control cells, as well as higher activity of cathepsins and higher receptor degradation activity. Consistently, we observed an increased number of lysosomes, accompanied by higher lysosomal degradative activity in CMT2B cells. Furthermore, we found increased migration and increased RAC1 and MMP-2 activation in CMT2B compared to control cells. To validate these data, we obtained sensory neurons from patient and control iPS cells, to confirm increased lysosomal protein expression and lysosomal activity in CMT2B-derived neurons. Altogether, these results demonstrate that in CMT2B patient-derived cells, the endocytic degradative pathway is altered, suggesting that higher lysosomal activity contributes to neurodegeneration occurring in CMT2B.
  • Rozov, Stanislav V.; Zant, Janneke; Gurevicius, Kestutis; Porkka-Heiskanen, Tarja; Panula, Pertti (2016)
    Aim: Under natural conditions diurnal rhythms of biological processes of the organism are synchronized with each other and to the environmental changes by means of the circadian system. Disturbances of the latter affect hormonal levels, sleep-wakefulness cycle and cognitive performance. To study mechanisms of such perturbations animal models subjected to artificial photoperiods are often used. The goal of current study was to understand the effects of circadian rhythm disruption, caused by a short light-dark cycle regime, on activity of the cerebral cortex in rodents. Methods: We used electroencephalogram to assess the distribution of vigilance states, perform spectral analysis, and estimate the homeostatic sleep drive. In addition, we analyzed spontaneous locomotion of C57BL/6J mice under symmetric, 22-, 21-, and 20-h-long light-dark cycles using video recording and tracking methods. Results and Conclusions: We found that shortening of photoperiod caused a significant increase of slow wave activity during non-rapid eye movement sleep suggesting an elevation of sleep pressure under such conditions. While the rhythm of spontaneous locomotion was completely entrained by all light-dark cycles tested, periodic changes in the power of the theta- and gamma-frequency ranges during wakefulness gradually disappeared under 22- and 21-h-long light-dark cycles. This was associated with a significant increase in the theta-gamma phase-amplitude coupling during wakefulness. Our results thus provide deeper understanding of the mechanisms underlying the impairment of learning and memory retention, which is associated with disturbed circadian regulation.
  • Chen, Zuyue; Wei, Hong; Sagalajev, Boriss; Koivisto, Ari; Pertovaara, Antti (2019)
    Background: The central amygdaloid nucleus (CeA) is involved in processing and descending regulation of pain. Amygdaloid mechanisms underlying pain processing and control are poorly known. Here we tested the hypothesis that perioperative CeA administration of tetrapentylammonium (TPA), a non-selective THIK-1 channel blocker and thereby inhibitor of microglia, attenuates development of chronic neuropathic pain and comorbid anxiety-like behavior. Methods: Rats with a spared nerve injury (SNI) model of neuropathy or sham operation had a chronic cannula for drug microinjections into the CeA or a control injection site. Monofilament test was used to evaluate pain, and light-dark box (LDB) to assess anxiety. Results: Perioperative CeA treatment with TPA (30 mu g/day up to the third postoperative day, D3) significantly attenuated the development of pain and anxiety-like behavior. In the late phase (> D14), CeA administration of TPA (3-30 mu g) failed to influence pain. Perioperative minocycline (microglia inhibitor; 25 mu g), MK-801 (an N-Methyl-D-aspartate receptor antagonist; 0.1 mu g), vehicle or TPA in a control injection site failed to attenuate pain development. Conclusions: Perioperative treatment of the CeA with TPA delayed development of neuropathic pain and comorbid anxiety-like behavior, while TPA treatment failed to influence maintenance of established neuropathic pain. The failures to attenuate pain development with CeA administrations of minocycline or MK-801 do not support the hypothesis that the TPA-induced prophylactic effect was due to inhibition of amygdaloid microglia or N-methyl-D-aspartate receptors. While TPA in the CeA proved to have a prophylactic effect on SNI-induced pain behavior, the underlying mechanism still remains to be studied. (c) 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.
  • Sanchez-Aguilera, Alberto; Wheeler, Diek W.; Jurado-Parras, Teresa; Valero, Manuel; Nokia, Miriam S.; Cid, Elena; Fernandez-Lamo, Ivan; Sutton, Nate; Garcia-Rincón, Daniel; de la Prida, Liset M.; Ascoli, Giorgio A. (2021)
    Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal-hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in . We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function.
  • Fernandez-Lopez, Blanca; Barreiro-Iglesias, Anton; Celina Rodicio, Maria (2016)
    Lampreys recover locomotion following a spinal cord injury (SCI). Glutamate is necessary to initiate and control locomotion and recent data suggest a crucial role for intraspinal neurons in functional recovery following SCI. We aimed to determine whether, in lampreys, axotomized spinal glutamatergic neurons, which lose glutamate immunoreactivity immediately after SCI, recover it later on and to study the long-term evolution and anatomical recovery of the spinal glutamatergic system after SCI. We used glutamate immunoreactivity to study changes in the glutamatergic system, tract-tracing to label axotomized neurons and TUNEL labelling to study cell death. Transections of the cord were made at the level of the fifth gill. TUNEL experiments indicated that cell death is a minor contributor to the initial loss of glutamate immunoreactivity. At least some of the axotomized neurons lose glutamate immunoreactivity, survive and recover glutamate immunoreactivity 1 week post-lesion (wpl). We observed a progressive increase in the number of glutamatergic neurons/processes until an almost complete anatomical recovery at 10 wpl. Among all the glutamatergic populations, the population of cerebrospinal fluid-contacting cells is the only one that never recovers. Our results indicate that full recovery of the glutamatergic system is not necessary for the restoration of function in lampreys.
  • Pohjanvirta, Raimo; Mahiout, Selma (2019)
    Previous studies have shown that several aryl hydrocarbon receptor (AHR) agonists, including β-naphthoflavone (BNF), elicit avoidance of novel food items in rodents, with this behavioral response displaying a similar doseresponse to hepatic induction of CYP1A1. The avoidance has been found to bear substantial similarity to conditioned taste avoidance/aversion (CTA). The present study set out to confirm the indispensability of AHR in the avoidance response, to verify whether vagal afferent fibers are involved in it, and to see if AHR signaling might interfere with the effect of the classic trigger of CTA, LiCl. To this end, globally AHR deficient (AHRKO) or vagotomized wildtype rats were treated by gavage with 60 mg/kg BNF or ip with 0.15M LiCl (4 ml/kg), and presented with chocolate which was either novel or familiar to them. Both the avoidance response and Cyp1a1 induction were missing in AHRKO rats. In contrast, Ahr+/− rats exhibited them in full, save for a single outlier. Total subdiaphragmatic vagotomy failed to interfere with the avoidance of novel or familiar chocolate or induction of Cyp1a1. After LiCl administration, male AHRKO rats showed a significantly mitigated suppression of chocolate consumption compared with wildtype animals (~60% vs. ~10% of control chocolate intake, respectively). A similar tendency was seen in females, but they were less responsive to LiCl. These findings corroborate AHR as a prerequisite of the BNF-induced novel food avoidance, prove vagal afferents unlikely mediators of this response, and imply an unforeseen involvement of AHR signaling in the thoroughly-characterized CTA instigated by LiCl.
  • Pyykkö, Ilmari; Manchaiah, Vinaya; Zou, Jing; Levo, Hilla; Kentala, Erna (2019)
    OBJECTIVES: The aim of the current study was to further collect evidence that would confirm the hypothesis that vestibular drop attacks (VDAs) could cause syncope in patients with Meniere's disease (MD). MATERIALS and METHODS: A cross-sectional survey design was employed in the present study. An Internet-based survey was administered on 602 individuals with MD. The mean age of the participants was 56.7 (25-75) years, and the mean duration of the disease was 12.4 (0.5-35) years. RESULTS: VDAs with varying severity were present among 307 (50.7%) patients and led to fall in 92 patients, and syncope occurred in 45 patients with VDA. The overall percentage of syncope due to MD was 4.7%. Factors, such as duration of disease, age, and gender of the patient, did not explain attacks of syncope. Migraine and headache were not associated with syncope. Syncope was witnessed in 23 and self-reported by 22 patients. Syncope was associated with frequent VDA, duration of VDA, and falls that occurred during VDA. Patients with syncope reported the experience as frightening, had reduced general health-related quality of life, had higher anxiousness scores, and suffered more from fatigue. They also experienced problems with work, employment, and social restrictions. CONCLUSION: Approximately 5% of patients with MD suffer from syncope, and syncope occurs among patients with VDA. In vestibular syncope, the sympathetic tone is lost, and baroreflex feedback is inhibited leading to fall and syncope. The consequences of vestibular syncope are severe, and patients face injuries and a significantly reduced quality of life.
  • Luo, Guo; Ambati, Aditya; Lin, Ling; Bonvalet, Melodie; Partinen, Markku; Ji, Xuhuai; Maecker, Holden Terry; Mignot, Emmanuel Jean-Marie (2018)
    Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4(+) T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA(273-287) (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17-31 and C-amidated but not native version of HCRT54-66 and HCRT86-97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3 beta TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA(273-287)-tetramers, suggesting molecular mimicry. This public CDR3 beta uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-alpha/beta CDR3 motifs of HCRT54-66-NH2 and HCRT86-97-NH2 tetramers were extensively shared: notably public CDR3 alpha, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-alpha/beta CDR3 sequences found in pHA(273-287), NP17-31, and HCRTNH2 tetramer-positive CD4(+) cells were also retrieved in single INF-gamma-secreting CD4(+) sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
  • Albert, Katrina; Renko, Juho-Matti; Mätlik, Kert; Airavaara, Mikko; Voutilainen, Merja H. (2019)
    Cerebral dopamine neurotrophic factor (CDNF) has shown therapeutic potential in rodent and non-human primate models of Parkinson's disease by protecting the dopamine neurons from degeneration and even restoring their phenotype and function. Previously, neurorestorative efficacy of CDNF in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease as well as diffusion of the protein in the striatum (STR) has been demonstrated and studied. Here, experiments were performed to characterize the diffusion and transport of supra-nigral CDNF in non-lesioned rats. We injected recombinant human CDNF to the substantia nigra (SN) of naive male Wistar rats and analyzed the brains 2, 6, and 24 h after injections. We performed immunohistochemical stainings using an antibody specific to human CDNF and radioactivity measurements after injecting iodinated CDNF. Unlike the previously reported striatonigral retrograde transport seen after striatal injection, active anterograde transport of CDNF to the STR could not be detected after nigral injection. There was, however, clear diffusion of CDNF to the brain areas surrounding the SN, and CDNF colocalized with tyrosine hydroxylase (TH)-positive neurons. Overall, our results provide insight on how CDNF injected to the SN may act in this region of the brain.
  • Kallijärvi, Jukka; Stratoulias, Vassilis; Virtanen, Kristel; Hietakangas, Ville; Heino, Tapio I.; Saarma, Mart (2012)
  • Turconi, Giorgio; Kopra, Jaakko; Võikar, Vootele; Kulesskaya, Natalia; Vilenius, Carolina; Piepponen, T. Petteri; Andressoo, Jaan-Olle (2020)
    Glial cell line-derived neurotrophic factor (GDNF) supports function and survival of dopamine neurons that degenerate in Parkinson's disease (PD). Ectopic delivery of GDNF in clinical trials to treat PD is safe but lacks significant therapeutic effect. In pre-clinical models, ectopic GDNF is effective but causes adverse effects, including downregulation of tyrosine hydroxylase, only a transient boost in dopamine metabolism, aberrant neuronal sprouting, and hyperactivity. Hindering development of GDNF mimetic increased signaling via GDNF receptor RET by activating mutations results in cancer. Safe and effective mode of action must be defined first in animal models to develop successful GDNF-based therapies. Previously we showed that about a 2-fold increase in endogenous GDNF expression is safe and results in increased motor and dopaminergic function and protection in a PD model in young animals. Recently, similar results were reported using a novel Gdnf mRNA-targeting strategy. Next, it is important to establish the safety of a long-term increase in endogenous GDNF expression. We report behavioral, dopamine system, and cancer analysis of five cohorts of aged mice with a 2-fold increase in endogenous GDNF. We found a sustained increase in dopamine levels, improvement in motor learning, and no side effects or cancer. These results support the rationale for further development of endogenous GDNF-based treatments and GDNF mimetic.
  • Popova, Dina; Agustsdottir, Arna; Lindholm, Jesse; Mazulis, Warns; Akamine, Yumiko; Castren, Eero; Karpova, Nina N. (2014)
  • Kopra, Jaakko; Villarta-Aguilera, Marian; Savolainen, Mari; Weingerl, Samo; Myohänen, Timo T.; Rannanpää, Saara; Salvatore, Michael E.; Andressoo, Jaan-Olle; Piepponen, T. Petteri (2018)
    Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum. We utilized two knock-in mouse strains to delineate contributions of GDNF and Ret signaling using MEN2B mice (constitutively active GDNF receptor Ret), and GDNF hypermorphic mice (enhanced endogenous GDNF expression). The duration of amphetamine-induced CPP was greatly enhanced in MEN2B mice, but not in the GDNF hypermorphic mice. The enhanced duration of CPP was correlated with increased tyrosine hydroxylase (TH) expression and dopamine content in the ventral striatum. Together, our results suggest that downstream components of GDNF signaling, in this case Ret, may mediate persistent drug-seeking behavior through increased TH expression and dopamine levels in the mesolimbic dopamine neurons. (C) 2017 Elsevier Ltd. All rights reserved.
  • Andalibi, Vafa; Hokkanen, Henri; Vanni, Simo (2019)
    Simulation of the cerebral cortex requires a combination of extensive domain-specific knowledge and efficient software. However, when the complexity of the biological system is combined with that of the software, the likelihood of coding errors increases, which slows model adjustments. Moreover, few life scientists are familiar with software engineering and would benefit from simplicity in form of a high-level abstraction of the biological model. Our primary aim was to build a scalable cortical simulation framework for personal computers. We isolated an adjustable part of the domain-specific knowledge from the software. Next, we designed a framework that reads the model parameters from comma-separated value files and creates the necessary code for Brian2 model simulation. This separation allows rapid exploration of complex cortical circuits while decreasing the likelihood of coding errors and automatically using efficient hardware devices. Next, we tested the system on a simplified version of the neocortical microcircuit proposed by Markram and colleagues (2015). Our results indicate that the framework can efficiently perform simulations using Python, C++, and GPU devices. The most efficient device varied with computer hardware and the duration and scale of the simulated system. The speed of Brian2 was retained despite an overlying layer of software. However, the Python and C++ devices inherited the single core limitation of Brian2. The CxSystem framework supports exploration of complex models on personal computers and thus has the potential to facilitate research on cortical networks and systems.
  • Matlashov, Mikhail E.; Vera, Jorge; Kasatkina, Ludmila A.; Khodakhah, Kamran; Verkhusha, Vladislav V. (2022)
    Near-infrared (NIR) genetically encoded calcium indicators (GECIs) are becoming powerful tools for neuroscience. Because of their spectral characteristics, the use of NIR GECIs helps to avoid signal loss from the absorption by body pigments, light-scattering, and autofluorescence in mammalian tissues. In addition, NIR GECIs do not suffer from cross-excitation artifacts when used with common fluorescent indicators and optogenetics actuators. Although several NIR GECIs have been developed, there is no NIR GECI currently available that would combine the high brightness in cells and photostability with small size and fast response kinetics. Here, we report a small FRET-based NIR fluorescent calcium indicator iGECInano. We characterize iGECInano in vitro, in non-neuronal mammalian cells, and primary mouse neurons. iGECInano demonstrates the improvement in the signal-to-noise ratio and response kinetics compared to other NIR GECIs.
  • Noei, Shahryar; Zouridis, Ioannis S.; Logothetis, Nikos K.; Panzeri, Stefano; Totah, Nelson K. (2022)
    The noradrenergic locus coeruleus (LC) is a controller of brain and behavioral states. Activating LC neurons en masse by electrical or optogenetic stimulation promotes a stereotypical "activated" cortical state of high-frequency oscillations. However, it has been recently reported that spontaneous activity of LC cell pairs has sparse yet structured time-averaged cross-correlations, which is unlike the highly synchronous neuronal activity evoked by stimulation. Therefore, LC population activity could consist of distinct multicell ensembles each with unique temporal evolution of activity. We used nonnegative matrix factorization (NMF) to analyze large populations of simultaneously recorded LC single units in the rat LC. NMF identified ensembles of spontaneously coactive LC neurons and their activation time courses. Since LC neurons selectively project to specific forebrain regions, we hypothesized that distinct ensembles activate during different cortical states. To test this hypothesis, we calculated band-limited power and spectrograms of local field potentials in cortical area 24a aligned to spontaneous activations of distinct LC ensembles. A diversity of state modulations occurred around activation of different LC ensembles, including a typical activated state with increased highfrequency power as well as other states including decreased high-frequency power. Thus-in contrast to the stereotypical activated brain state evoked by en masse LC stimulation-spontaneous activation of distinct LC ensembles is associated with a multitude of cortical states.
  • Wiencke, Kathleen; Horstmann, Annette; Mathar, David; Villringer, Arno; Neumann, Jane (2020)
    Computational modeling of dopamine transmission is challenged by complex underlying mechanisms. Here we present a new computational model that (I) simultaneously regards release, diffusion and uptake of dopamine, (II) considers multiple terminal release events and (III) comprises both synaptic and volume transmission by incorporating the geometry of the synaptic cleft. We were able to validate our model in that it simulates concentration values comparable to physiological values observed in empirical studies. Further, although synaptic dopamine diffuses into extra-synaptic space, our model reflects a very localized signal occurring on the synaptic level, i.e. synaptic dopamine release is negligibly recognized by neighboring synapses. Moreover, increasing evidence suggests that cognitive performance can be predicted by signal variability of neuroimaging data (e.g. BOLD). Signal variability in target areas of dopaminergic neurons (striatum, cortex) may arise from dopamine concentration variability. On that account we compared spatio-temporal variability in a simulation mimicking normal dopamine transmission in striatum to scenarios of enhanced dopamine release and dopamine uptake inhibition. We found different variability characteristics between the three settings, which may in part account for differences in empirical observations. From a clinical perspective, differences in striatal dopaminergic signaling contribute to differential learning and reward processing, with relevant implications for addictive- and compulsive-like behavior. Specifically, dopaminergic tone is assumed to impact on phasic dopamine and hence on the integration of reward-related signals. However, in humans DA tone is classically assessed using PET, which is an indirect measure of endogenous DA availability and suffers from temporal and spatial resolution issues. We discuss how this can lead to discrepancies with observations from other methods such as microdialysis and show how computational modeling can help to refine our understanding of DA transmission. Author summary The dopaminergic system of the brain is very complex and affects various cognitive domains like memory, learning and motor control. Alterations have been observed e.g. in Parkinson's or Huntington's Disease, ADHD, addiction and compulsive disorders, such as pathological gambling and also in obesity. We present a new computational model that allows to simulate the process of dopamine transmission from dopaminergic neurons originated in source brain regions like the VTA to target areas such as the striatum on a synaptic and on a larger, volume-spanning level. The model can further be used for simulations of dopamine related diseases or pharmacological interventions. In general, computational modeling helps to extend our understanding, gained from empirical research, to situations were in vivo measurements are not feasible.
  • Oliviero, Claudio; Heinonen, Mari; Valros, Anna; Peltoniemi, Olli (2010)
  • Goodman, Timothy; Nayar, Stuart G.; Clare, Shaun; Mikolajczak, Marta; Rice, Ritva; Mansour, Suzanne; Bellusci, Saverio; Hajihosseini, Mohammad K. (2020)
    New neurons are generated in the postnatal rodent hypothalamus, with a subset of tanycytes in the third ventricular (3V) wall serving as neural stem/progenitor cells. However, the precise stem cell niche organization, the intermediate steps and the endogenous regulators of postnatal hypothalamic neurogenesis remain elusive. Quantitative lineage-tracing in vivo revealed that conditional deletion of fibroblast growth factor 10 (Fgf10) from Fgf10-expressing beta-tanycytes at postnatal days (P)4-5 results in the generation of significantly more parenchymal cells by P28, composed mostly of ventromedial and dorsomedial neurons and some glial cells, which persist into adulthood. A closer scrutiny in vivo and ex vivo revealed that the 3V wall is not static and is amenable to cell movements. Furthermore, normally beta-tanycytes give rise to parenchymal cells via an intermediate population of alpha-tanycytes with transient amplifying cell characteristics. Loss of Fgf10 temporarily attenuates the amplification of beta-tanycytes but also appears to delay the exit of their alpha-tanycyte descendants from the germinal 3V wall. Our findings suggest that transience of cells through the alpha-tanycyte domain is a key feature, and Fgf10 is a negative regulator of postnatal hypothalamic neurogenesis.
  • Leopold, Anna V.; Shcherbakova, Daria; Verkhusha, Vladislav V. (2019)
    Understanding how neuronal activity patterns in the brain correlate with complex behavior is one of the primary goals of modern neuroscience. Chemical transmission is the major way of communication between neurons, however, traditional methods of detection of neurotransmitter and neuromodulator transients in mammalian brain lack spatiotemporal precision. Modern fluorescent biosensors for neurotransmitters and neuromodulators allow monitoring chemical transmission in vivo with millisecond precision and single cell resolution. Changes in the fluorescent biosensor brightness occur upon neurotransmitter binding and can be detected using fiber photometry, stationary microscopy and miniaturized head-mounted microscopes. Biosensors can be expressed in the animal brain using adeno-associated viral vectors, and their cell-specific expression can be achieved with Cre-recombinase expressing animals. Although initially fluorescent biosensors for chemical transmission were represented by glutamate biosensors, nowadays biosensors for GABA, acetylcholine, glycine, norepinephrine, and dopamine are available as well. In this review, we overview functioning principles of existing intensiometric and ratiometric biosensors and provide brief insight into the variety of neurotransmitter-binding proteins from bacteria, plants, and eukaryotes including G-protein coupled receptors, which may serve as neurotransmitter-binding scaffolds. We next describe a workflow for development of neurotransmitter and neuromodulator biosensors. We then discuss advanced setups for functional imaging of neurotransmitter transients in the brain of awake freely moving animals. We conclude by providing application examples of biosensors for the studies of complex behavior with the single-neuron precision.