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1.
Neuropsychopharmacology ; 46(6): 1172-1182, 2021 05.
Article in English | MEDLINE | ID: mdl-33007779

ABSTRACT

The basolateral amygdala (BLA) modulates the consolidation of dorsal hippocampus (DH)-dependent spatial and dorsolateral striatum (DLS)-dependent cued-response memories, often in competition with one another. Evidence suggests that a critical mechanism for BLA influences on memory consolidation is via effects on activity-regulated cytoskeletal-associated protein (ARC) in downstream brain regions. However, the circuitry by which the BLA modulates ARC in multiple competing memory systems remains unclear. Prior evidence indicates that optogenetic stimulation of BLA projections to the medial entorhinal cortex (mEC) enhances the consolidation of spatial learning and impairs the consolidation of cued-response learning, suggesting this pathway provides a circuit for favoring one system over another. Therefore, we hypothesized the BLA-mEC pathway mediates effects on downstream ARC-based synaptic plasticity related to these competing memory systems. To address this, male and female Sprague-Dawley rats underwent spatial or cued-response Barnes maze training and, 45 min later, were sacrificed for ARC analysis in synaptoneurosomes from the DH and DLS. Initial experiments found that spatial training alone increased ARC levels in the DH above those observed in control rats and rats that underwent a cued-response version of the task. Postspatial training optogenetic stimulation of the BLA-mEC pathway altered the balance of ARC expression in the DH vs. DLS, specifically shifting the balance in favor of the DH-based spatial memory system, although the precise region of ARC changes differed by sex. These findings suggest that BLA-mEC pathway influences on ARC in downstream regions are a mechanism by which the BLA can favor one memory system over another.


Subject(s)
Basolateral Nuclear Complex , Amygdala , Animals , Entorhinal Cortex , Female , Hippocampus , Male , Rats , Rats, Sprague-Dawley , Spatial Memory
2.
J Neurodev Disord ; 12(1): 27, 2020 09 28.
Article in English | MEDLINE | ID: mdl-32988374

ABSTRACT

BACKGROUND: Rett syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive, and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome. METHODS: We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task. RESULTS: Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT. CONCLUSIONS: Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.


Subject(s)
Rett Syndrome , Animals , Auditory Perception , Female , Learning , Methyl-CpG-Binding Protein 2/genetics , Mice , Mice, Transgenic , Rats , Rett Syndrome/complications , Rett Syndrome/genetics
3.
Neural Plast ; 2016: 4273280, 2016.
Article in English | MEDLINE | ID: mdl-27957346

ABSTRACT

Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction.


Subject(s)
Amygdala/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/biosynthesis , Cytoskeletal Proteins/biosynthesis , Fear/physiology , Nerve Tissue Proteins/biosynthesis , Receptors, N-Methyl-D-Aspartate/biosynthesis , Vagus Nerve Stimulation/methods , Amygdala/drug effects , Animals , Conditioning, Psychological/drug effects , Conditioning, Psychological/physiology , Cytoskeletal Proteins/antagonists & inhibitors , Excitatory Amino Acid Antagonists/pharmacology , Extinction, Psychological/drug effects , Extinction, Psychological/physiology , Fear/drug effects , Fear/psychology , Male , Nerve Tissue Proteins/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Vagus Nerve Stimulation/psychology
4.
J Vis Exp ; (102): e53032, 2015 Aug 21.
Article in English | MEDLINE | ID: mdl-26325100

ABSTRACT

Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been maintaining the behavior. There is close correspondence between fear and human anxiety, and therefore studies of extinction learning might provide insight into the biological nature of anxiety-related disorders such as post-traumatic stress disorder, and they might help to develop strategies to treat them. Preclinical research aims to aid extinction learning and to induce targeted plasticity in extinction circuits to consolidate the newly formed memory. Vagus nerve stimulation (VNS) is a powerful approach that provides tight temporal and circuit-specific release of neurotransmitters, resulting in modulation of neuronal networks engaged in an ongoing task. VNS enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here, we provide a detailed protocol for the preparation of custom-made parts and the surgical procedures required for VNS in rats. Using this protocol we show how VNS can facilitate the extinction of conditioned fear responses in an auditory fear conditioning task. In addition, we provide evidence that VNS modulates synaptic plasticity in the pathway between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA), which is involved in the expression and modulation of extinction memory.


Subject(s)
Extinction, Psychological/physiology , Neuronal Plasticity/physiology , Vagus Nerve Stimulation/methods , Amygdala/physiology , Animals , Fear/physiology , Humans , Prefrontal Cortex/physiology , Rats
5.
Neuron ; 76(2): 325-37, 2012 Oct 18.
Article in English | MEDLINE | ID: mdl-23083736

ABSTRACT

Fragile X syndrome (FXS) is the leading inherited cause of autism and intellectual disability. Aberrant synaptic translation has been implicated in the etiology of FXS, but most lines of research on therapeutic strategies have targeted protein synthesis indirectly, far upstream of the translation machinery. We sought to perturb p70 ribosomal S6 kinase 1 (S6K1), a key translation initiation and elongation regulator, in FXS model mice. We found that genetic reduction of S6K1 prevented elevated phosphorylation of translational control molecules, exaggerated protein synthesis, enhanced mGluR-dependent long-term depression (LTD), weight gain, and macro-orchidism in FXS model mice. In addition, S6K1 deletion prevented immature dendritic spine morphology and multiple behavioral phenotypes, including social interaction deficits, impaired novel object recognition, and behavioral inflexibility. Our results support the model that dysregulated protein synthesis is the key causal factor in FXS and that restoration of normal translation can stabilize peripheral and neurological function in FXS.


Subject(s)
Behavior, Animal/physiology , Fragile X Syndrome/pathology , Fragile X Syndrome/prevention & control , Fragile X Syndrome/physiopathology , Gene Expression Regulation/genetics , Ribosomal Protein S6 Kinases, 70-kDa/deficiency , Synapses/genetics , Analysis of Variance , Animals , Biophysics , Dendritic Spines/classification , Dendritic Spines/physiology , Disease Models, Animal , Electric Stimulation , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , Exploratory Behavior/physiology , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/genetics , Hippocampus/pathology , In Vitro Techniques , Interpersonal Relations , Long-Term Synaptic Depression/drug effects , Long-Term Synaptic Depression/genetics , Male , Maze Learning/physiology , Membrane Potentials/drug effects , Membrane Potentials/genetics , Methoxyhydroxyphenylglycol/analogs & derivatives , Methoxyhydroxyphenylglycol/pharmacology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Motor Activity/genetics , Mutation/genetics , Neurons/classification , Neurons/pathology , Patch-Clamp Techniques , Phenotype , Phosphorylation/genetics , Recognition, Psychology/physiology , Ribosomal Protein S6 Kinases, 70-kDa/genetics , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Rotarod Performance Test , Synapses/drug effects , TOR Serine-Threonine Kinases/genetics
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