Hypothalamic Dopamine Neurons Control Sensorimotor Behavior by Modulating Brainstem Premotor Nuclei in Zebrafish

Barrios, Joshua; Wang, Wei‐Chun; England, Roman; Reifenberg, Erica; Douglass, Adam D.

doi:10.1016/j.cub.2020.09.002

Cited by 43 publications

(35 citation statements)

References 65 publications

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“…Sensorimotor gating deficits are a hallmark of many schizophrenia-like symptoms in CNS disorders. Dopaminergic neurons in the hypothalamus (Barrios et al, 2020), cholinergic or non-cholinergic pedunculopontine tegmental nucleus neurons in the midbrain (Fulcher et al, 2020), and D2 receptor-expressing neurons in the nucleus accumbens (Shilling et al, 2006;Berger et al, 2011;Yamaguchi et al, 2015) could also be involved in sensorimotor regulation, and the functional impairments caused by brain calcification might be responsible for the defects in Slc20a2-HO mice.…”

Section: Neurobehavioral Abnormalities and Their Relations With Brain Calcificationsmentioning

confidence: 99%

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Ren

Shen

et al. 2021

Front. Genet.

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BackgroundPrimary familial brain calcification (PFBC, OMIM#213600), also known as Fahr’s disease, is a rare autosomal dominant or recessive neurodegenerative disorder characterized by bilateral and symmetrical microvascular calcifications affecting multiple brain regions, particularly the basal ganglia (globus pallidus, caudate nucleus, and putamen) and thalamus. The most common clinical manifestations include cognitive impairment, neuropsychiatric signs, and movement disorders. Loss-of-function mutations in SLC20A2 are the major genetic causes of PFBC.ObjectiveThis study aimed to investigate whether Slc20a2 knockout mice could recapitulate the dynamic processes and patterns of brain calcification and neurological symptoms in patients with PFBC. We comprehensively evaluated brain calcifications and PFBC-related behavioral abnormalities in Slc20a2-deficient mice.MethodsBrain calcifications were analyzed using classic calcium-phosphate staining methods. The Morris water maze, Y-maze, and fear conditioning paradigms were used to evaluate long-term spatial learning memory, working memory, and episodic memory, respectively. Sensorimotor gating was mainly assessed using the prepulse inhibition of the startle reflex program. Spontaneous locomotor activity and motor coordination abilities were evaluated using the spontaneous activity chamber, cylinder test, accelerating rotor-rod, and narrowing balance beam tests.ResultsSlc20a2 homozygous knockout (Slc20a2-HO) mice showed congenital and global developmental delay, lean body mass, skeletal malformation, and a high proportion of unilateral or bilateral eye defects. Brain calcifications were detected in the hypothalamus, ventral thalamus, and midbrain early at postnatal day 80 in Slc20a2-HO mice, but were seldom found in Slc20a2 heterozygous knockout (Slc20a2-HE) mice, even at extremely old age. Slc20a2-HO mice exhibited spatial learning memory impairments and sensorimotor gating deficits while exhibiting normal working and episodic memories. The general locomotor activity, motor balance, and coordination abilities were not statistically different between Slc20a2-HO and wild-type mice after adjusting for body weight, which was a major confounding factor in our motor function evaluations.ConclusionThe human PFBC-related phenotypes were highly similar to those in Slc20a2-HO mice. Therefore, Slc20a2-HO mice might be suitable for the future evaluation of neuropharmacological intervention strategies targeting cognitive and neuropsychiatric impairments.

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Section: Neurobehavioral Abnormalities and Their Relations With Brain Calcificationsmentioning

confidence: 99%

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Ren

Shen

et al. 2021

Front. Genet.

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“…Brain and spinal motor circuits are under the influence of neuromodulators. For example, the dopaminergic system is an important player in the motor control of vertebrates (Grillner and Robertson, 2016), including zebrafish larvae (Lambert et al, 2012;McPherson et al, 2016;Barrios et al, 2020). Both in mammals and teleost fish, dopaminergic neurons can be identified by the expression of the gene tyrosine hydroxylase (th), encoding one of the enzymes necessary for dopamine synthesis.…”

Section: Modulation Of Exploratory and Foraging Behaviorsmentioning

confidence: 99%

“…Zebrafish has two paralogous th genes (th1 and th2) displaying partially non-overlapping expression patterns (Filippi et al, 2010). The activity of subpopulations of hypothalamic th1 + and th2 + dopaminergic neurons is correlated with swimming (Jay et al, 2015;Reinig et al, 2017;Barrios et al, 2020). Ablation of hypothalamic dopaminergic neurons decreased the frequency of swimming bouts (McPherson et al, 2016;Barrios et al, 2020).…”

Section: Modulation Of Exploratory and Foraging Behaviorsmentioning

confidence: 99%

Neuromodulation and Behavioral Flexibility in Larval Zebrafish: From Neurotransmitters to Circuits

Corradi

Filosa

2021

Front. Mol. Neurosci.

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Animals adapt their behaviors to their ever-changing needs. Internal states, such as hunger, fear, stress, and arousal are important behavioral modulators controlling the way an organism perceives sensory stimuli and reacts to them. The translucent zebrafish larva is an ideal model organism for studying neuronal circuits regulating brain states, owning to the possibility of easy imaging and manipulating activity of genetically identified neurons while the animal performs stereotyped and well-characterized behaviors. The main neuromodulatory circuits present in mammals can also be found in the larval zebrafish brain, with the advantage that they contain small numbers of neurons. Importantly, imaging and behavioral techniques can be combined with methods for generating targeted genetic modifications to reveal the molecular underpinnings mediating the functions of such circuits. In this review we discuss how studying the larval zebrafish brain has contributed to advance our understanding of circuits and molecular mechanisms regulating neuromodulation and behavioral flexibility.

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“…Two genes, th1 and th2 , encode the TH enzyme in zebrafish, and both Th1 and Th2 proteins are highly similar to the mammalian TH [ 33 ]. Immunohistochemical analysis of Th1 was performed as it is widely expressed in all brain regions, whereas Th2 is localized to hypothalamic, posterior tubercular, and preoptic regions of the zebrafish brain [ 34 ]. In two of the sensory and behavioral epicenters of the brain, the telencephalon and olfactory bulbs, we observed considerable reductions in Th1 at both the mRNA and protein level in parla ot510 adult zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Loss of parla Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish

et al. 2021

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The presenilin-associated rhomboid-like (PARL) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The PARL gene product is a mitochondrial intramembrane cleaving protease that acts on a number of mitochondrial proteins involved in mitochondrial morphology, apoptosis, and mitophagy. To date, functional and genetic studies of PARL have been mainly performed in mammals. However, little is known about PARL function and its role in dopaminergic (DA) neuron development in vertebrates. The zebrafish genome comprises two PARL paralogs: parla and parlb. Here, we established a loss-of-function mutation in parla via CRISPR/Cas9-mediated mutagenesis. We examined DA neuron numbers in the adult brain and expression of genes associated with DA neuron function in larvae and adults. We show that loss of parla function results in loss of DA neurons, mainly in the olfactory bulb. Changes in the levels of tyrosine hydroxylase transcripts supported this neuronal loss. Expression of fis1, a gene involved in mitochondrial fission, was increased in parla mutants. Finally, we showed that loss of parla function translates into impaired olfaction and altered locomotion parameters. These results suggest a role for parla in the development and/or maintenance of DA neuron function in zebrafish.

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Hypothalamic Dopamine Neurons Control Sensorimotor Behavior by Modulating Brainstem Premotor Nuclei in Zebrafish

Cited by 43 publications

References 65 publications

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Slc20a2-Deficient Mice Exhibit Multisystem Abnormalities and Impaired Spatial Learning Memory and Sensorimotor Gating but Normal Motor Coordination Abilities

Neuromodulation and Behavioral Flexibility in Larval Zebrafish: From Neurotransmitters to Circuits

Loss of parla Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish

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