Reduced Firing of Nucleus Accumbens Parvalbumin Interneurons Impairs Risk Avoidance in DISC1 Transgenic Mice

AbstractA strong animal survival instinct is to approach objects and situations that are of benefit and to avoid risk. In humans, a large proportion of mental disorders are accompanied by impairments in risk avoidance. One of the most important genes involved in mental disorders is disrupted-in-schizophrenia-1 (DISC1), and animal models in which this gene has some level of dysfunction show emotion-related impairments. However, it is not known whether DISC1 mouse models have an impairment in avoiding potential risks. In the present study, we used DISC1-N terminal truncation (DISC1-NTM) mice to investigate risk avoidance and found that these mice were impaired in risk avoidance on the elevated plus maze (EPM) and showed reduced social preference in a three-chamber social interaction test. Following EPM tests, c-Fos expression levels indicated that the nucleus accumbens (NAc) was associated with risk-avoidance behavior in DISC1-NTM mice. In addition, in vivo electrophysiological recordings following tamoxifen administration showed that the firing rates of fast-spiking neurons (FS) in the NAc were significantly lower in DISC1-NTM mice than in wild-type (WT) mice. In addition, in vitro patch clamp recording revealed that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc of DISC1-NTM mice than in WT controls. The impairment of risk avoidance in DISC1-NTM mice was rescued using optogenetic tools that activated NAcPV neurons. Finally, inhibition of the activity of NAcPV neurons in PV-Cre mice mimicked the risk-avoidance impairment found in DISC1-NTM mice during tests on the elevated zero maze. Taken together, our findings confirm an impairment in risk avoidance in DISC1-NTM mice and suggest that reduced excitability of NAcPV neurons is responsible.

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Parvalbumin interneurons in the nucleus accumbens regulate impairment of risk avoidance in DISC1 transgenic mice

10.1101/2020.09.10.291450 ◽

2020 ◽

Author(s):

Xinyi Zhou ◽

Bifeng Wu ◽

Qian Xiao ◽

Wei He ◽

Ying Zhou ◽

...

Keyword(s):

Nucleus Accumbens ◽

Cognitive Abilities ◽

Social Preference ◽

Patch Clamp Recording ◽

Risk Avoidance ◽

Electrophysiological Recordings ◽

Potential Risks ◽

Frequency Of Action Potentials

AbstractOne strong survival instinct in animals is to approach things that are of benefit and avoid risk. In humans, a large portion of mental disorders are accompanied by cognition-related impairments including the inability to recognize potential risks. One of the most important genes involved in risk behavior is disrupted-in-schizophrenia-1 (DISC1), and animal models where this gene has some dysfunction show cognitive impairments. However, whether DISC1 mice models have an impairment in avoiding potential risks is still not fully understood. In the present study, we used DISC1-N terminal truncation (DISC1-NTM) mice to study cognitive abilities related to potential risks. We found that DISC1-NTM mice were impaired in risk avoidance on the elevated plus maze (EPM) test, and showed impairment in social preference in a three-chamber social interaction test. Staining for c-Fos following the EPM indicated that the nucleus accumbens (NAc) was associated with risk avoidance behavior in DISC1-NTM mice. Meanwhile, in vivo electrophysiological recordings showed that firing rates of fast spiking neurons (FS) in the NAc significantly decreased in DISC1-NTM mice following tamoxifen administration. In addition, theta band power was lower when mice shuttled from the safe (closed) arms to the risky (open) arms, an effect which disappeared after induction of the truncated DISC1 gene. Furthermore, we found through in vitro patch clamp recording that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc of DISC1-NTM mice than their wild-type littermates. Risk-avoidance impairments in DISC1-NTM mice were rescued using optogenetic tools that activated NAcPV neurons. Finally, we inhibited activitiy of NAcPV neurons in PV-Cre mice, which mimicked the risk-avoidance impairment found in the DISC1-NTM mice during tests on the elevated zero maze. Taken together, our findings confirmed a cognitive impairment in DISC1-NTM mice related to risk recognition and suggests that reduced excitability of NAcPV neurons may be responsible.

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Ex Vivo Brain Preparation to Analyze Vocal Pathways of Xenopus Frogs

Cold Spring Harbor Protocols ◽

10.1101/pdb.prot106872 ◽

2021 ◽

Vol 2021 (9) ◽

pp. pdb.prot106872

Author(s):

Ayako Yamaguchi

Keyword(s):

Neural Activity ◽

Ex Vivo ◽

Neural Circuitry ◽

Neural Basis ◽

Vocal Production ◽

Basic Principles ◽

Electrophysiological Recordings ◽

The Brain

Understanding the neural basis of behavior is a challenging task for technical reasons. Most methods of recording neural activity require animals to be immobilized, but neural activity associated with most behavior cannot be recorded from an anesthetized, immobilized animal. Using amphibians, however, there has been some success in developing in vitro brain preparations that can be used for electrophysiological and anatomical studies. Here, we describe an ex vivo frog brain preparation from which fictive vocalizations (the neural activity that would have produced vocalizations had the brain been attached to the muscle) can be elicited repeatedly. When serotonin is applied to the isolated brains of male and female African clawed frogs, Xenopus laevis, laryngeal nerve activity that is a facsimile of those that underlie sex-specific vocalizations in vivo can be readily recorded. Recently, this preparation was successfully used in other species within the genus including Xenopus tropicalis and Xenopus victorianus. This preparation allows a variety of techniques to be applied including extracellular and intracellular electrophysiological recordings and calcium imaging during vocal production, surgical and pharmacological manipulation of neurons to evaluate their impact on motor output, and tract tracing of the neural circuitry. Thus, the preparation is a powerful tool with which to understand the basic principles that govern the production of coherent and robust motor programs in vertebrates.

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NO inhibits supraoptic oxytocin and vasopressin neurons via activation of GABAergic synaptic inputs

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.6.r1815 ◽

2001 ◽

Vol 280 (6) ◽

pp. R1815-R1822 ◽

Cited By ~ 71

Author(s):

Javier E. Stern ◽

Mike Ludwig

Keyword(s):

Neuronal Excitability ◽

Cell Types ◽

Synaptic Activity ◽

No Donor ◽

Whole Cell Patch Clamp ◽

Electrophysiological Recordings ◽

Neuronal Types ◽

Vasopressin Neurons

To study modulatory actions of nitric oxide (NO) on GABAergic synaptic activity in hypothalamic magnocellular neurons in the supraoptic nucleus (SON), in vitro and in vivo electrophysiological recordings were obtained from identified oxytocin and vasopressin neurons. Whole cell patch-clamp recordings were obtained in vitro from immunochemically identified oxytocin and vasopressin neurons. GABAergic synaptic activity was assessed in vitro by measuring GABAA miniature inhibitory postsynaptic currents (mIPSCs). The NO donor and precursor sodium nitroprusside (SNP) and l-arginine, respectively, increased the frequency and amplitude of GABAA mIPSCs in both cell types ( P ≤ 0.001). Retrodialysis of SNP (50 mM) onto the SON in vivo inhibited the activity of both neuronal types ( P ≤ 0.002), an effect that was reduced by retrodialysis of the GABAA-receptor antagonist bicuculline (2 mM, P≤ 0.001). Neurons activated by intravenous infusion of 2 M NaCl were still strongly inhibited by SNP. These results suggest that NO inhibition of neuronal excitability in oxytocin and vasopressin neurons involves pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON.

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Nutraceuticals in Thyroidology: A Review of in Vitro, and in Vivo Animal Studies

Nutrients ◽

10.3390/nu12051337 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1337

Author(s):

Salvatore Benvenga ◽

Silvia Martina Ferrari ◽

Giusy Elia ◽

Francesca Ragusa ◽

Armando Patrizio ◽

...

Keyword(s):

Clinical Practice ◽

Animal Studies ◽

Experimental Studies ◽

Omega 3 ◽

Complementary Medicines ◽

Pathological Conditions ◽

Potential Risks ◽

Dietary Components

Nutraceuticals are defined as a food, or parts of a food, that provide medical or health benefits, including the prevention of different pathological conditions, and thyroid diseases, or the treatment of them. Nutraceuticals have a place in complementary medicines, being positioned in an area among food, food supplements, and pharmaceuticals. The market of certain nutraceuticals such as thyroid supplements has been growing in the last years. In addition, iodine is a fundamental micronutrient for thyroid function, but also other dietary components can have a key role in clinical thyroidology. Here, we have summarized the in vitro, and in vivo animal studies present in literature, focusing on the commonest nutraceuticals generally encountered in the clinical practice (such as carnitine, flavonoids, melatonin, omega-3, resveratrol, selenium, vitamins, zinc, and inositol), highlighting conflicting results. These experimental studies are expected to improve clinicians’ knowledge about the main supplements being used, in order to clarify the potential risks or side effects and support patients in their use.

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Direct Excitation of Mitral Cells Via Activation of α1-Noradrenergic Receptors in Rat Olfactory Bulb Slices

Journal of Neurophysiology ◽

10.1152/jn.2001.86.5.2173 ◽

2001 ◽

Vol 86 (5) ◽

pp. 2173-2182 ◽

Cited By ~ 45

Author(s):

Abdallah Hayar ◽

Phillip M. Heyward ◽

Thomas Heinbockel ◽

Michael T. Shipley ◽

Matthew Ennis

Keyword(s):

Olfactory Bulb ◽

Locus Coeruleus ◽

Equilibrium Potential ◽

Channel Blockers ◽

Mitral Cells ◽

Patch Clamp Recording ◽

Whole Cell ◽

Inward Current

The main olfactory bulb receives a significant modulatory noradrenergic input from the locus coeruleus. Previous in vivo and in vitro studies showed that norepinephrine (NE) inputs increase the sensitivity of mitral cells to weak olfactory inputs. The cellular basis for this action of NE is not understood. The goal of this study was to investigate the effect of NE and noradrenergic agonists on the excitability of mitral cells, the main output cells of the olfactory bulb, using whole cell patch-clamp recording in vitro. The noradrenergic agonists, phenylephrine (PE, 10 μM), isoproterenol (Isop, 10 μM), and clonidine (3 μM), were used to test for the functional presence of α1-, β-, and α2-receptors, respectively, on mitral cells. None of these agonists affected olfactory nerve (ON)–evoked field potentials recorded in the glomerular layer, or ON-evoked postsynaptic currents recorded in mitral cells. In whole cell voltage-clamp recordings, NE (30 μM) induced an inward current (54 ± 7 pA, n= 16) with an EC50 of 4.7 μM. Both PE and Isop also produced inward currents (22 ± 4 pA, n = 19, and 29 ± 9 pA, n = 8, respectively), while clonidine produced no effect ( n = 6). In the presence of TTX (1 μM), and blockers of excitatory and inhibitory fast synaptic transmission [gabazine 5 μM, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) 10 μM, and (±)-2-amino-5-phosphonopentanoic acid (APV) 50 μM], the inward current induced by PE persisted (EC50 = 9 μM), whereas that of Isop was absent. The effect of PE was also observed in the presence of the Ca2+ channel blockers, cadmium (100 μM) and nickel (100 μM). The inward current caused by PE was blocked when the interior of the cell was perfused with the nonhydrolyzable GDP analogue, GDPβS, indicating that the α1 effect is mediated by G-protein coupling. The current-voltage relationship in the absence and presence of PE indicated that the current induced by PE decreased near the equilibrium potential for potassium ions. In current-clamp recordings from bistable mitral cells, PE shifted the membrane potential from the downstate (−52 mV) toward the upstate (−40 mV), and significantly increased spike generation in response to perithreshold ON input. These findings indicate that NE excites mitral cells directly via α1 receptors, an effect that may underlie, at least in part, increased mitral cell responses to weak ON input during locus coeruleus activation in vivo.

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Acceleration of conduction velocity linked to clustering of nodal components precedes myelination

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1419099112 ◽

2015 ◽

Vol 112 (3) ◽

pp. E321-E328 ◽

Cited By ~ 33

Author(s):

Sean A. Freeman ◽

Anne Desmazières ◽

Jean Simonnet ◽

Marie Gatta ◽

Friederike Pfeiffer ◽

...

Keyword(s):

Hippocampal Neurons ◽

Pyramidal Neurons ◽

Axonal Conduction ◽

Electrophysiological Recordings ◽

Single Axon ◽

Physiological Relevance ◽

Saltatory Conduction ◽

Insight Into

High-density accumulation of voltage-gated sodium (Nav) channels at nodes of Ranvier ensures rapid saltatory conduction along myelinated axons. To gain insight into mechanisms of node assembly in the CNS, we focused on early steps of nodal protein clustering. We show in hippocampal cultures that prenodes (i.e., clusters of Nav channels colocalizing with the scaffold protein ankyrinG and nodal cell adhesion molecules) are detected before myelin deposition along axons. These clusters can be induced on purified neurons by addition of oligodendroglial-secreted factor(s), whereas ankyrinG silencing prevents their formation. The Nav isoforms Nav1.1, Nav1.2, and Nav1.6 are detected at prenodes, with Nav1.6 progressively replacing Nav1.2 over time in hippocampal neurons cultured with oligodendrocytes and astrocytes. However, the oligodendrocyte-secreted factor(s) can induce the clustering of Nav1.1 and Nav1.2 but not of Nav1.6 on purified neurons. We observed that prenodes are restricted to GABAergic neurons, whereas clustering of nodal proteins only occurs concomitantly with myelin ensheathment on pyramidal neurons, implying separate mechanisms of assembly among different neuronal subpopulations. To address the functional significance of these early clusters, we used single-axon electrophysiological recordings in vitro and showed that prenode formation is sufficient to accelerate the speed of axonal conduction before myelination. Finally, we provide evidence that prenodal clusters are also detected in vivo before myelination, further strengthening their physiological relevance.

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Lens refilling and endocapsular polymerization of an injectable intraocular lens: In vitro and in vivo study of potential risks and benefits

Journal of Cataract & Refractive Surgery ◽

10.1016/s0886-3350(13)80149-6 ◽

1994 ◽

Vol 20 (2) ◽

pp. 115-123 ◽

Cited By ~ 50

Author(s):

Hans- J. Hettlich ◽

Klaus Lucke ◽

Mary N. Asiyo-Vogel ◽

Manuela Schulte ◽

Alfred Vogel

Keyword(s):

Intraocular Lens ◽

In Vivo Study ◽

Risks And Benefits ◽

Lens Refilling ◽

Potential Risks

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Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition

Journal of Neurophysiology ◽

10.1152/jn.00238.2016 ◽

2016 ◽

Vol 116 (3) ◽

pp. 1093-1103 ◽

Cited By ~ 11

Author(s):

Michael E. Authement ◽

Ludovic D. Langlois ◽

Haifa Kassis ◽

Shawn Gouty ◽

Matthieu Dacher ◽

...

Keyword(s):

Behavioral Plasticity ◽

Drugs Of Abuse ◽

Patch Clamp Recording ◽

Whole Cell Patch Clamp ◽

Synaptic Changes ◽

Induced Changes ◽

And Behavior ◽

H3 Acetylation

Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9. Interestingly, HDACi incubation also increased levels of Ac-H3K9 and triggered GABAergic and glutamatergic plasticities in DA neurons of saline-treated rats. Our results suggest that acute morphine-induced changes in VTA DA activity and synaptic transmission engage HDAC2 activity locally in the VTA to maintain synaptic modifications through histone hypoacetylation.

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