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1.
Neurobiol Stress ; 13: 100262, 2020 Nov.
Article in English | MEDLINE | ID: mdl-33344715

ABSTRACT

Acute physical or psychological stress can elicit adaptive behaviors that allow an organism maintain homeostasis. However, intense and/or prolonged stressors often have the opposite effect, resulting in maladaptive behaviors and curbing goal-directed action; in the extreme, this may contribute to the development of psychiatric conditions like generalized anxiety disorder, major depressive disorder, or post-traumatic stress disorder. While treatment of these disorders generally focuses on reducing reactivity to potentially threatening stimuli, there are in fact impairments across multiple domains including valence, arousal, and cognition. Here, we use the genetically stress-susceptible 129S1 mouse strain to explore the effects of stress across multiple domains. We find that 129S1 mice exhibit a potentiated neuroendocrine response across many environments and paradigms, and that this is associated with reduced exploration, neophobia, decreased novelty- and reward-seeking, and spatial learning and memory impairments. Taken together, our results suggest that the 129S1 strain may provide a useful model for elucidating mechanisms underlying myriad aspects of stress-linked psychiatric disorders as well as potential treatments that may ameliorate symptoms.

2.
J Neurophysiol ; 113(4): 1184-94, 2015 Feb 15.
Article in English | MEDLINE | ID: mdl-25429123

ABSTRACT

Hilar ectopic dentate granule cells (DGCs) are a salient feature of aberrant plasticity in human temporal lobe epilepsy (TLE) and most rodent models of the disease. Recent evidence from rodent TLE models suggests that hilar ectopic DGCs contribute to hyperexcitability within the epileptic hippocampal network. Here we investigate the intrinsic excitability of DGCs from humans with TLE and the rat pilocarpine TLE model with the objective of comparing the neurophysiology of hilar ectopic DGCs to their normotopic counterparts in the granule cell layer (GCL). We recorded from 36 GCL and 7 hilar DGCs from human TLE tissue. Compared with GCL DGCs, hilar DGCs in patient tissue exhibited lower action potential (AP) firing rates, more depolarized AP threshold, and differed in single AP waveform, consistent with an overall decrease in excitability. To evaluate the intrinsic neurophysiology of hilar ectopic DGCs, we made recordings from retrovirus-birthdated, adult-born DGCs 2-4 mo after pilocarpine-induced status epilepticus or sham treatment in rats. Hilar DGCs from epileptic rats exhibited higher AP firing rates than normotopic DGCs from epileptic or control animals. They also displayed more depolarized resting membrane potential and wider AP waveforms, indicating an overall increase in excitability. The contrasting findings between disease and disease model may reflect differences between the late-stage disease tissue available from human surgical specimens and the earlier disease stage examined in the rat TLE model. These data represent the first neurophysiological characterization of ectopic DGCs from human hippocampus and prospectively birthdated ectopic DGCs in a rodent TLE model.


Subject(s)
Action Potentials , Dentate Gyrus/physiopathology , Epilepsy, Temporal Lobe/physiopathology , Neurons/physiology , Adult , Animals , Dentate Gyrus/cytology , Female , Humans , Male , Middle Aged , Rats , Rats, Sprague-Dawley
3.
Behav Brain Res ; 267: 42-5, 2014 Jul 01.
Article in English | MEDLINE | ID: mdl-24657592

ABSTRACT

Fragile X syndrome (FXS) is a common inherited cause of intellectual disability that results from a CGG repeat expansion in the FMR1 gene. Large repeat expansions trigger both transcriptional and translational suppression of Fragile X protein (FMRP) production. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an allelic neurodegenerative disease caused by smaller "pre-mutation" CGG repeat expansions that enhance FMR1 transcription but lead to translational inefficiency and reduced FMRP expression in animal models. Sensorimotor gating as measured by pre-pulse inhibition (PPI) is altered in both FXS patients and Fmr1 knock out (KO) mice. Similarly, FXTAS patients have demonstrated PPI deficits. Recent work suggests there may be overlapping synaptic defects between Fmr1 KO and CGG knock-in premutation mouse models (CGG KI). We therefore sought to interrogate PPI in CGG KI mice. Using a quiet PPI protocol more akin to human testing conditions, we find that Fmr1 KO animals have significantly impaired PPI. Using this same protocol, we find CGG KI mice demonstrate an age-dependent impairment in PPI compared to wild type (WT) controls. This study describes a novel phenotype in CGG KI mice that can be used in future therapeutic development targeting premutation associated symptoms.


Subject(s)
Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/physiopathology , Prepulse Inhibition/physiology , Sensory Gating/physiology , Acoustic Stimulation , Age Factors , Animals , Auditory Perception/physiology , Disease Models, Animal , Fragile X Mental Retardation Protein/genetics , Gene Knock-In Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Trinucleotide Repeat Expansion
4.
Genes Brain Behav ; 7(6): 629-38, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18363861

ABSTRACT

The Scn8a gene encodes the alpha-subunit of Na(v)1.6, a neuronal voltage-gated sodium channel. Mice homozygous for mutations in the Scn8a gene exhibit motor impairments. Recently, we described a human family with a heterozygous protein truncation mutation in SCN8A. Rather than motor impairment, neuropsychological abnormalities were more common, suggesting a role for Scn8a in a more diverse range of behaviors. Here, we characterize mice heterozygous for a null mutation of Scn8a (Scn8a(+/-)mice) in a number of behavioral paradigms. We show that Scn8a(+/-)mice exhibit greater conditioned freezing in the Pavlovian fear conditioning paradigm but no apparent abnormalities in other learning and memory paradigms including the Morris water maze and conditioned taste avoidance paradigm. Furthermore, we find that Scn8a(+/-)mice exhibit more pronounced avoidance of well-lit, open environments as well as more stress-induced coping behavior. Together, these data suggest that Scn8a plays a critical role in emotional behavior in mice. Although the behavioral phenotype observed in the Scn8a(+/-)mice only partially models the abnormalities in the human family, we anticipate that the Scn8a(+/-)mice will serve as a valuable tool for understanding the biological basis of emotion and the human diseases in which abnormal emotional behavior is a primary component.


Subject(s)
Brain Chemistry/genetics , Brain/metabolism , Emotions/physiology , Nerve Tissue Proteins/genetics , Neurocognitive Disorders/genetics , Sodium Channels/genetics , Animals , Avoidance Learning/physiology , Behavior, Animal/physiology , Brain/physiopathology , Cell Membrane/genetics , Cell Membrane/metabolism , Conditioning, Psychological/physiology , Female , Heterozygote , Male , Maze Learning/physiology , Membrane Potentials/genetics , Mice , Mice, Knockout , NAV1.6 Voltage-Gated Sodium Channel , Neurons/metabolism
5.
Genes Brain Behav ; 7(2): 203-13, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17640289

ABSTRACT

Transgenic mice in which the tetracycline transactivator (tTA) is driven by the forebrain-specific calcium-calmodulin-dependent kinase II alpha promoter (CaMKII alpha-tTA mice) are used to study the molecular genetics of many behaviors. These mice can be crossed with other transgenic mice carrying a transgene of interest coupled to the tetracycline-responsive promoter element to produce mice with forebrain-specific expression of the transgene under investigation. The value of using CaMKII alpha-tTA mice to study behavior, however, is dependent on the CaMKII alpha-tTA mice themselves lacking a behavioral phenotype with respect to the behaviors being studied. Here we present data that suggest CaMKII alpha-tTA mice have a behavioral phenotype distinct from that of their wild-type (WT) littermates. Most strikingly, we find that CaMKII alpha-tTA mice, both those with a C57BL/6NTac genetic background (B6-tTA) and those with a 129S6B6F1/Tac hybrid genetic background (F1-tTA), exhibit decreased locomotor activity compared with WT littermates that could be misinterpreted as altered anxiety-like behavior. Despite this impairment, neither B6-tTA nor F1-tTA mice perform differently than their WT littermates in two commonly used learning and memory paradigms - Pavlovian fear conditioning and Morris water maze. Additionally, we find data regarding motor coordination and balance to be mixed: B6-tTA mice, but not F1-tTA mice, exhibit impaired performance on the accelerating rotarod and both perform as well as their WT littermates on the balance beam.


Subject(s)
Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Exploratory Behavior , Maze Learning/physiology , Motor Activity/genetics , Promoter Regions, Genetic , Tetracycline/metabolism , Trans-Activators/genetics , Animals , Anxiety , Darkness , Light , Mice , Mice, Inbred C57BL , Mice, Transgenic , Protein Processing, Post-Translational , Proteomics
6.
Life Sci ; 68(22-23): 2489-93, 2001 Apr 27.
Article in English | MEDLINE | ID: mdl-11392617

ABSTRACT

We used gene targeting to generate mice lacking the M1 muscarinic acetylcholine receptor. These mice exhibit a decreased susceptibility to pilocarpine-induced seizures, loss of regulation of M-current potassium channel activity and of a specific calcium channel pathway in sympathetic neurons, a loss of the positive chronotropic and inotropic responses to the novel muscarinic agonist McN-A-343, and impaired learning in a hippocampal-dependent test of spatial memory.


Subject(s)
Calcium Channels/metabolism , Heart/physiology , Neurons/physiology , Potassium Channels/metabolism , Receptors, Muscarinic/metabolism , Signal Transduction/physiology , Animals , Cells, Cultured , Electrophysiology , GTP-Binding Proteins/metabolism , Gene Targeting , Heart/drug effects , Hippocampus/cytology , Hippocampus/physiology , Humans , Learning/physiology , Memory/physiology , Mice , Mice, Knockout , Muscarinic Agonists/pharmacology , Neurons/drug effects , Oxotremorine/pharmacology , Pilocarpine/pharmacology , Rats , Receptor, Muscarinic M1 , Receptors, Muscarinic/genetics , Seizures/chemically induced , Signal Transduction/genetics , Telencephalon/cytology , Telencephalon/physiology
7.
J Neurosci ; 19(23): 10595-602, 1999 Dec 01.
Article in English | MEDLINE | ID: mdl-10575055

ABSTRACT

We previously showed that the associative enhancement of Aplysia siphon sensorimotor synapses in a cellular analog of classical conditioning is disrupted by infusing the Ca(2+) chelator 1, 2-bis(2-aminophenoxy)ethane-N,N-N',N'-tetraacetic acid into the postsynaptic motor neuron before training or by training in the presence of the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (APV). Our earlier experiments with APV used a nondifferential training protocol, in which different preparations were used for associative and nonassociative training. In the present experiments we extended our investigation of the role of NMDA receptor type potentiation in learning in Aplysia to differential conditioning. A cellular analog of differential conditioning was performed with a reduced preparation that consisted of the CNS plus two pedal nerves. A siphon motor neuron and two siphon sensory neurons, both of which were presynaptically connected to the motor neuron, were impaled with sharp microelectrodes. One sensorimotor synapse received paired stimulation with a conditioned stimulus (brief activation of a single sensory neuron) and an unconditioned stimulus (pedal nerve shock), whereas the other sensorimotor synapse received unpaired stimulation. Training in normal artificial seawater (ASW) resulted in significant differential enhancement of synapses that received the paired stimulation. Training in APV blocked this differential synaptic enhancement. A comparison of the present data with the data from earlier experiments that used nondifferential training is consistent with the possibility that differential training comprises competition between the presynaptic sensory neurons. Synaptic competition may contribute significantly to the associative effect of paired stimulation in the differential training paradigm.


Subject(s)
2-Amino-5-phosphonovalerate/pharmacology , Aplysia/physiology , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Excitatory Amino Acid Antagonists/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Electric Stimulation , Motor Neurons/physiology , Nervous System Physiological Phenomena , Recruitment, Neurophysiological/physiology , Synapses/physiology , Tail/innervation
9.
Science ; 278(5337): 467-71, 1997 Oct 17.
Article in English | MEDLINE | ID: mdl-9334306

ABSTRACT

Long-term potentiation (LTP) is considered an important neuronal mechanism of learning and memory. Currently, however, there is no direct experimental link between LTP of an identified synapse and learning. A cellular analog of classical conditioning in Aplysia was used to determine whether this form of invertebrate learning involves N-methyl-D-aspartate (NMDA)-type LTP. The NMDA receptor-antagonist dl-2-amino-5-phosphonovalerate significantly disrupted synaptic enhancement after associative training but did not disrupt synaptic enhancement after nonassociative training. Thus, classical conditioning in Aplysia appears to be mediated, in part, by LTP due to activation of NMDA-related receptors.


Subject(s)
Conditioning, Classical , Long-Term Potentiation , Motor Neurons/physiology , Neurons, Afferent/physiology , Synapses/physiology , 2-Amino-5-phosphonovalerate/pharmacology , Animals , Aplysia , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials , Long-Term Potentiation/drug effects , Models, Neurological , Motor Neurons/drug effects , Neurons, Afferent/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Serotonin/physiology , Synapses/drug effects
10.
Proc Natl Acad Sci U S A ; 93(18): 9931-6, 1996 Sep 03.
Article in English | MEDLINE | ID: mdl-8790434

ABSTRACT

Classical conditioning of Aplysia's siphon-withdrawal reflex is thought to be due to a presynaptic mechanism-activity-dependent presynaptic facilitation of sensorimotor connections. Recent experiments with sensorimotor synapses in dissociated cell culture, however, provide an alternative cellular mechanism for classical conditioning-Hebbian long-term potentiation (LTP) of sensorimotor connections. Induction of Hebbian LTP of these connections is mediated by activation of N-methyl-D-aspartate-related receptors and requires the postsynaptic elevation of intracellular Ca2+. To determine whether the enhancement of sensorimotor synapses during classical conditioning in Aplysia-like LTP of sensorimotor synapses in culture-also depends upon the elevation of postsynaptic Ca2+, we carried out experiments involving the cellular analog of classical conditioning of siphon withdrawal. We examined changes in the strength of monosynaptic siphon sensorimotor connections in the abdominal ganglion of Aplysia following paired presentations of sensory neuron activation and tail nerve shock. This training regimen resulted in significant enhancement of the monosynaptic sensorimotor excitatory postsynaptic potential, as compared with the sensorimotor excitatory postsynaptic potential in preparations that received only test stimulation. Infusing the motor neuron with 1,2-bis(2-aminophenoxy)ethane-N,N-N',N'-tetraacetic acid, a specific chelator of intracellular Ca2+, prior to paired stimulation training blocked this synaptic enhancement. Our results implicate a postsynaptic, possibly Hebbian, mechanism in classical conditioning in Aplysia.


Subject(s)
Aplysia/physiology , Calcium/metabolism , Conditioning, Classical , Synapses , Animals , Conditioning, Classical/drug effects , Egtazic Acid/analogs & derivatives , Egtazic Acid/pharmacology , Evoked Potentials , Learning/physiology , Memory/physiology , Motor Neurons/physiology , Neurons, Afferent/physiology
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