Molecular fMRI of Serotonin Transport

Hai, Aviad; Cai, Lili; Lee, Taekwan; Lelyveld, Victor S.; Jasanoff, Alan

doi:10.1016/j.neuron.2016.09.048

Cited by 38 publications

(33 citation statements)

References 53 publications

(68 reference statements)

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“…This suggests that these regions were recruited by FLX treatment to restore the PSD behavioral phenotype. The lateral septum receives dense 5-HT innervation and is particularly sensitive to SSRIs [60,61]. In PSD mice, chronic FLX and combination treatments but not exercise alone induced GABAergic FosB + cells, consistent with a chronic anxiolytic role for septal interneurons [62][63][64].…”

Section: Chronic Flx Reverses Stroke-induced Imbalance In Neuronal Acmentioning

confidence: 74%

Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment

Vahid-Ansari

Albert

2018

Neurotherapeutics

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Poststroke depression (PSD) is a common outcome of stroke that limits recovery and is only partially responsive to chronic antidepressant treatment. In order to elucidate changes in the cortical-limbic circuitry associated with PSD and its treatment, we examined a novel mouse model of persistent PSD. Focal endothelin-1-induced ischemia of the left medial prefrontal cortex (mPFC) in male C57BL6 mice resulted in a chronic anxiety and depression phenotype. Here, we show severe cognitive impairment in spatial learning and memory in the stroke mice. The behavioral and cognitive phenotypes were reversed by chronic (4-week) treatment with fluoxetine, alone or with voluntary exercise (free-running wheel), but not by exercise alone. To assess chronic cellular activation, FosB cells were co-labeled for markers of glutamate/pyramidal (VGluT1-3/CaMKIIα), γ-aminobutyric acid (GAD67), and serotonin (TPH). At 6 weeks poststroke versus sham (or 4 days poststroke), left mPFC stroke induced widespread FosB activation, more on the right (contralesional) than on the left side. Stroke activated glutamate cells of the mPFC, nucleus accumbens, amygdala, hippocampus, and raphe serotonin neurons. Chronic fluoxetine balanced bilateral neuronal activity, reducing total FosB and FosB/CamKII cells (mPFC, nucleus accumbens), and unlike exercise, increasing FosB/GAD67 cells (septum, amygdala) or both (hippocampus, raphe). In summary, chronic antidepressant but not exercise mediates recovery in this unilateral ischemic PSD model that is associated with region-specific reversal of stroke-induced pyramidal cell hyperactivity and increase in γ-aminobutyric acidergic activity. Targeted brain stimulation to restore brain activity could provide a rational approach for treating clinical PSD.

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Section: Chronic Flx Reverses Stroke-induced Imbalance In Neuronal Acmentioning

confidence: 74%

Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment

Vahid-Ansari

Albert

2018

Neurotherapeutics

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“…In comparison to the reported methodologies for 5-HT dynamic imaging such as FSCV 13 , microdialysis 14 , and paramagnetic 5-HT binding proteins for MRI 42 , nIRHT nanosensors are promising high spatiotemporal fluorescence imaging probes for studying 5-HT neuromodulation, which provide sub-micrometer spatial resolution, reversibility, photostability, and selectivity against 5-HT metabolites and receptor-targeting drugs. Furthermore, SWNT fluoresce in a unique near-infrared window (1000-1300 nm) which reduces photon scattering and enhances imaging penetration depths, enabling through-cranium 22 and in vivo imaging 39 .…”

Section: Discussionmentioning

confidence: 99%

High Throughput Evolution of Near Infrared Serotonin Nanosensors

Jeong¹,

Yang²,

Beyene³

et al. 2019

Preprint

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Release and reuptake of neuromodulator serotonin, 5-HT, is central to mood regulation and neuropsychiatric disorders, whereby imaging serotonin is of fundamental importance to study the brain's serotonin signaling system. We introduce a reversible near-infrared nanosensor for serotonin (nIRHT), for which synthetic molecular recognition toward serotonin is systematically evolved from ssDNA-carbon nanotube constructs generated from large libraries of 6.9 × 10 10 unique ssDNA sequences. nIRHT produces a ~200% fluorescence enhancement upon exposure to serotonin with a Kd = 6.3 µM affinity.nIRHT shows selective responsivity towards serotonin over serotonin analogs, metabolites, and receptortargeting drugs, and a 5-fold increased affinity for serotonin over dopamine. Further, nIRHT can be introduced into the brain extracellular space in acute slice, and can be used to image exogenous serotonin reversibly. Our results suggest evolution of nanosensors could be generically implemented to rapidly develop other neuromodulator probes, and that these probes can image neuromodulator dynamics at spatiotemporal scales compatible with endogenous neuromodulation.Serotonin, or 5-hydroxytryptamine (5-HT) is a monoamine neuromodulator that plays diverse roles in the central nervous system and is critically implicated in the etiology and treatment of mood and psychiatric disorders 1 . 5-HT also plays critical roles in modulating memory and learning 2, 3 , and in the regulation of mood 4 , sleep 5 , and appetite 5 . As such, aberrations in 5-HT signaling are thought to underlie multiple mental health disorders including major depressive disorder 6 , bipolar disorder 7 , autism 8 , schizophrenia 9 , anxiety 10 , and addiction 11 . Classical neurotransmission occurs through rapid activation of ligand-gated ion channels in which neurotransmitter signaling is confined at the synaptic cleft and thus to singular synaptic partners 12 . However, 5-HT acts primarily as a neuromodulator and may undergo signaling through extrasynaptic diffusion, enabling few neurons to affect broader networks of neuronal activity through 5-HT volume transmission. As such, there is great interest in monitoring the spatial component of 5-HT modulation in addition to its temporal dynamics. Current methods for measuring 5-HT include tools adapted from analytical chemistry to measure 5-HT in the brain extracellular space with varying levels of selectivity and spatiotemporal resolution: fast-scan cyclic voltammetry leverages redox chemistry to enable rapid temporal measurement of 5-HT by inserting a carbon electrode into brain tissue 13 .Microdialysis is an analytical chemistry method in which fluid samples from brain tissue are subject to downstream analysis with chromatography 14 . Recently, a field-effect transistor sensor modified with a 5-HT aptamer was reported to exhibit a highly sensitive and selective electrochemical response to 5-HT in physiological conditions 15 . However, previous methods suffer from limited spatial resolution, and microdialysis sampling oc...

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“…to assess and quantify the reuptake rates of 5HT transporters). 23 Perspectives for development of further NT-SCA classes…”

Section: Practical Challenges In Functional Molecular Imaging Using Nmentioning

confidence: 99%

“…Genetically encoded, protein-based SCAs proved to be very efficient and capable of providing essential information on DA or 5HT fluctuations with high specificity. 20,22,23 They possess great selectivity and capacity for tuning the binding affinity for specific target molecules. However, the currently developed generation of mutants contains paramagnetic Fe 3+ , which gives rise to low longitudinal relaxivity of these proteins and hence low latitude for MRI signal change induction.…”

Section: Practical Challenges In Functional Molecular Imaging Using Nmentioning

confidence: 99%

Strategies for sensing neurotransmitters with responsive MRI contrast agents

Angelovski

Tóth

2017

Chem. Soc. Rev.

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A great deal of research involving multidisciplinary approaches is currently dedicated to the understanding of brain function. The complexity of physiological processes that underlie neural activity is the greatest hurdle to faster advances. Among imaging techniques, MRI has great potential to enable mapping of neural events with excellent specificity, spatiotemporal resolution and unlimited tissue penetration depth. To this end, molecular imaging approaches using neurotransmitter-sensitive MRI agents have appeared recently to study neuronal activity, along with the first successful in vivo MRI studies. Here, we review the pioneering steps in the development of molecular MRI methods that could allow functional imaging of the brain by sensing the neurotransmitter activity directly. We provide a brief overview of other imaging and analytical methods to detect neurotransmitter activity, and describe the approaches to sense neurotransmitters by means of molecular MRI agents. Based on these initial steps, further progress in probe chemistry and the emergence of innovative imaging methods to directly monitor neurotransmitters can be envisaged.

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Molecular fMRI of Serotonin Transport

Cited by 38 publications

References 53 publications

Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment

Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment

High Throughput Evolution of Near Infrared Serotonin Nanosensors

Strategies for sensing neurotransmitters with responsive MRI contrast agents

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