Serotonergic modulation of walking in Drosophila

AbstractTo navigate complex environments, animals must generate highly robust, yet flexible, locomotor behaviors. For example, walking speed must be tailored to the needs of a particular environment: Not only must animals choose the correct speed and gait, they must also rapidly adapt to changing conditions, and respond to sudden and surprising new stimuli. Neuromodulators, particularly the small biogenic amine neurotransmitters, allow motor circuits to rapidly alter their output by changing their functional connectivity. Here we show that the serotonergic system in the vinegar fly, Drosophilamelanogaster, can modulate walking speed in a variety of contexts and in response to sudden changes in the environment. These multifaceted roles of serotonin in locomotion are differentially mediated by a family of serotonergic receptors with distinct activities and expression patterns.

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Protein and gene markers of metabolic dysfunction and inflammation together associate with functional connectivity in reward and motor circuits in depression

Brain Behavior and Immunity ◽

10.1016/j.bbi.2020.05.013 ◽

2020 ◽

Vol 88 ◽

pp. 193-202 ◽

Cited By ~ 1

Author(s):

David R. Goldsmith ◽

Mandakh Bekhbat ◽

Ngoc-Anh Le ◽

Xiangchuan Chen ◽

Bobbi J. Woolwine ◽

...

Keyword(s):

Functional Connectivity ◽

Metabolic Dysfunction ◽

Gene Markers ◽

Motor Circuits

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Differential Changes in Functional Connectivity of Striatum-Prefrontal and Striatum-Motor Circuits in Premanifest Huntington’s Disease

Neurodegenerative Diseases ◽

10.1159/000501616 ◽

2019 ◽

Vol 19 (2) ◽

pp. 78-87 ◽

Cited By ~ 5

Author(s):

Martin Kronenbuerger ◽

Jun Hua ◽

Jee Y.A. Bang ◽

Kia E. Ultz ◽

Xinyuan Miao ◽

...

Keyword(s):

Functional Connectivity ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Cag Repeat ◽

Compensatory Mechanism ◽

Motor Score ◽

Cortical Areas ◽

Motor Circuits ◽

Neurophysiological Studies ◽

Cortical Regions

Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder. The striatum is one of the first brain regions that show detectable atrophy in HD. Previous studies using functional magnetic resonance imaging (fMRI) at 3 tesla (3 T) revealed reduced functional connectivity between striatum and motor cortex in the prodromal period of HD. Neuroanatomical and neurophysiological studies have suggested segregated corticostriatal pathways with distinct loops involving different cortical regions, which may be investigated using fMRI at an ultra-high field (7 T) with enhanced sensitivity compared to lower fields. Objectives: We performed fMRI at 7 T to assess functional connectivity between the striatum and several chosen cortical areas including the motor and prefrontal cortex, in order to better understand brain changes in the striatum-cortical pathways. Method: 13 manifest subjects (age 51 ± 13 years, cytosine-adenine-guanine [CAG] repeat 45 ± 5, Unified Huntington’s Disease Rating Scale [UHDRS] motor score 32 ± 17), 8 subjects in the close-to-onset premanifest period (age 38 ± 10 years, CAG repeat 44 ± 2, UHDRS motor score 8 ± 2), 11 subjects in the far-from-onset premanifest period (age 38 ± 11 years, CAG repeat 42 ± 2, UHDRS motor score 1 ± 2), and 16 healthy controls (age 44 ± 15 years) were studied. The functional connectivity between the striatum and several cortical areas was measured by resting state fMRI at 7 T and analyzed in all participants. Results: Compared to controls, functional connectivity between striatum and premotor area, supplementary motor area, inferior frontal as well as middle frontal regions was altered in HD (all p values <0.001). Specifically, decreased striatum-motor connectivity but increased striatum-prefrontal connectivity were found in premanifest HD subjects. Altered functional connectivity correlated consistently with genetic burden, but not with clinical scores. Conclusions: Differential changes in functional connectivity of striatum-prefrontal and striatum-motor circuits can be found in early and premanifest HD. This may imply a compensatory mechanism, where additional cortical regions are recruited to subserve functions that have been impaired due to HD pathology. Our results suggest the potential value of functional connectivity as a marker for future clinical trials in HD.

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Structural and functional connectivity of motor circuits after perinatal stroke: A machine learning study

NeuroImage Clinical ◽

10.1016/j.nicl.2020.102508 ◽

2020 ◽

Vol 28 ◽

pp. 102508

Author(s):

Helen L. Carlson ◽

Brandon T. Craig ◽

Alicia J. Hilderley ◽

Jacquie Hodge ◽

Deepthi Rajashekar ◽

...

Keyword(s):

Machine Learning ◽

Functional Connectivity ◽

Learning Study ◽

Perinatal Stroke ◽

Motor Circuits

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Cingulo-Opercular Control Network Supports Disused Motor Circuits in Standby Mode

10.1101/2020.09.03.275479 ◽

2020 ◽

Author(s):

Dillan J. Newbold ◽

Evan M. Gordon ◽

Timothy O. Laumann ◽

Nicole A. Seider ◽

David F. Montez ◽

...

Keyword(s):

Functional Connectivity ◽

Spontaneous Activity ◽

Functional Mri ◽

Executive Control ◽

Resting State ◽

Control Network ◽

Whole Brain ◽

Motor Circuits ◽

Standby Mode ◽

Control Regions

AbstractWhole-brain resting-state functional MRI (rs-fMRI) during two weeks of limb constraint revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula (1). Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions.SignificanceMany studies have examined plasticity in the primary somatosensory and motor cortex during disuse, but little is known about how disuse impacts the brain outside of primary cortical areas. We leveraged the whole-brain coverage of resting-state functional MRI (rs-fMRI) to discover that disuse drives plasticity of distant executive control regions in the cingulo-opercular network (CON). Two complementary analyses, pulse censoring and pulse addition, demonstrated that increased functional connectivity between the CON and disused motor regions was driven by large, spontaneous pulses of activity in the CON and disused motor regions. These results point to a previously unknown role for the CON in supporting motor plasticity and reveal spontaneous activity pulses as a novel mechanism for reorganizing the brain’s functional connections.

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Regional distribution of serotonergic receptors: a systems neuroscience perspective on the downstream effects of the multimodal-acting antidepressant vortioxetine on excitatory and inhibitory neurotransmission

CNS Spectrums ◽

10.1017/s1092852915000486 ◽

2015 ◽

Vol 21 (2) ◽

pp. 162-183 ◽

Cited By ~ 18

Author(s):

Alan L. Pehrson ◽

Theepica Jeyarajah ◽

Connie Sanchez

Keyword(s):

Conceptual Framework ◽

Selective Serotonin Reuptake Inhibitors ◽

Expression Patterns ◽

Receptor Expression ◽

Gabaergic Interneuron ◽

Medium Spiny Neurons ◽

Serotonergic Receptors ◽

Spiny Neurons ◽

Glutamate Neurotransmission ◽

Interneuron Activity

Previous work from this laboratory hypothesized that the multimodal antidepressant vortioxetine enhances cognitive function through a complex mechanism, using serotonergic (5-hydroxytryptamine, 5-HT) receptor actions to modulate gamma-butyric acid (GABA) and glutamate neurotransmission in key brain regions like the prefrontal cortex (PFC) and hippocampus. However, serotonergic receptors have circumscribed expression patterns, and therefore vortioxetine’s effects on GABA and glutamate neurotransmission will probably be regionally selective. In this article, we attempt to develop a conceptual framework in which the effects of 5-HT, selective serotonin reuptake inhibitors (SSRIs), and vortioxetine on GABA and glutamate neurotransmission can be understood in the PFC and striatum—2 regions with roles in cognition and substantially different 5-HT receptor expression patterns. Thus, we review the anatomy of the neuronal microcircuitry in the PFC and striatum, anatomical data on 5-HT receptor expression within these microcircuits, and electrophysiological evidence on the effects of 5-HT on the behavior of each cell type. This analysis suggests that 5-HT and SSRIs will have markedly different effects within the PFC, where they will induce mixed effects on GABA and glutamate neurotransmission, compared to the striatum, where they will enhance GABAergic interneuron activity and drive down the activity of medium spiny neurons. Vortioxetine is expected to reduce GABAergic interneuron activity in the PFC and concomitantly increase cortical pyramidal neuron firing. However in the striatum, vortioxetine is expected to increase activity at GABAergic interneurons and have mixed excitatory and inhibitory effects in medium spiny neurons. Thus the conceptual framework developed here suggests that vortioxetine will have regionally selective effects on GABA and glutamate neurotransmission.

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Exercise alters resting-state functional connectivity of motor circuits in parkinsonian rats

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2014.08.016 ◽

2015 ◽

Vol 36 (1) ◽

pp. 536-544 ◽

Cited By ~ 19

Author(s):

Zhuo Wang ◽

Yumei Guo ◽

Kalisa G. Myers ◽

Ryan Heintz ◽

Yu-Hao Peng ◽

...

Keyword(s):

Functional Connectivity ◽

Resting State ◽

Resting State Functional Connectivity ◽

Motor Circuits

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Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems

10.1101/253310 ◽

2018 ◽

Cited By ~ 1

Author(s):

Michael V. Lombardo ◽

Bonnie Auyeung ◽

Tiziano Pramparo ◽

Angélique Quartier ◽

Jérémie Courraud ◽

...

Keyword(s):

Cell Differentiation ◽

Functional Connectivity ◽

Neuronal Development ◽

Expression Patterns ◽

Fetal Brain ◽

Adult Brain ◽

Impact Excitation ◽

Social Brain ◽

Default Mode

AbstractMany early-onset neurodevelopmental conditions such as autism affect males more frequently than females and affect corresponding domains such as social cognition, social-communication, language, emotion, and reward. Testosterone is well-known for its role as a sex-related biological mechanism and affects these conditions and domains of functioning. Developmentally, testosterone may sex-differentially impact early fetal brain development by influencing early neuronal development and synaptic mechanisms behind cortical circuit formation, particularly for circuits that later develop specialized roles in such cognitive domains. Here we find that variation in fetal testosterone (FT) exerts sex-specific effects on later adolescent functional connectivity between social brain default mode network (DMN) subsystems. Increased FT is associated with dampening of functional connectivity between DMN subsystems in adolescent males, but has no effect in females. To isolate specific prenatal neurobiological mechanisms behind this effect, we examined changes in gene expression identified following a treatment with a potent androgen, dihydrotestosterone (DHT) in an in-vitro model of human neural stem cell (hNSC). We previously showed that DHT-dysregulates genes enriched with known syndromic causes for autism and intellectual disability. DHT dysregulates genes in hNSCs involved in early neurodevelopmental processes such as neurogenesis, cell differentiation, regionalization, and pattern specification. A significant number of these DHT-dysregulated genes shows spatial expression patterns in the adult brain that highly correspond to the spatial layout of the cortical midline DMN subsystem. These DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation/inhibition imbalance. Focusing on MEF2C, we find replicable upregulation of expression after DHT treatment as well as dysregulated expression in induced pluripotent stem cells and neurons of individuals with autism. This work highlights sex-specific prenatal androgen influence on social brain DMN circuitry and autism-related mechanisms and suggests that such influence may impact early neurodevelopmental processes (e.g., neurogenesis, cell differentiation) and later developing synaptic processes.

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Serotonin modulates learning content-specific neuroplasticity of functional brain networks

10.1101/2021.01.15.426779 ◽

2021 ◽

Author(s):

Manfred Klöbl ◽

René Seiger ◽

Thomas Vanicek ◽

Patricia Handschuh ◽

Murray Bruce Reed ◽

...

Keyword(s):

Functional Connectivity ◽

Underlying Mechanism ◽

Learning Effects ◽

Semantic Learning ◽

Learning Content ◽

Daily Dose ◽

Functional Brain Networks ◽

Brain Functional Connectivity ◽

Serotonergic Modulation

AbstractLearning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity. Animal models emphasized the crucial role of serotonin in neuroplasticity particularly for emotional relearning, but comparable studies in humans are scarce. Assessing the translation of learning effects from animals to humans, 99 healthy subjects underwent six weeks of emotional or semantic learning and subsequent relearning and three resting-state acquisitions for functional connectivity estimation. During relearning, subjects received either a daily dose of the selective serotonin reuptake inhibitor escitalopram or placebo. The influence of escitalopram on functional connectivity was connection- and learning content-dependent, with potentiation of decreases during emotional and increases during semantic learning. The directedness of these effects indicates serotonergic modulation of emotional feedback routes. These results demonstrate that escitalopram intake during relearning facilitates content-dependent network adaptations and support the conclusion that enhanced neuroplasticity might be the major underlying mechanism in psychiatric therapies.

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