ABSTRACT
Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory, and excitatory neurons suggests that each circuit motif may be controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a genetically encoded GRP sensor, optogenetic anterograde stimulation, and trans-synaptic tracing, we reveal that GRP regulates VIP cells most likely via extrasynaptic diffusion from several local and long-range sources. In vivo photometry and CRISPR-Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.
Subject(s)
Auditory Cortex/metabolism , Bombesin/metabolism , Fear/physiology , Memory/physiology , Nerve Net/metabolism , Amino Acid Sequence , Animals , Calcium/metabolism , Calcium Signaling , Conditioning, Classical , Gastrin-Releasing Peptide/chemistry , Gastrin-Releasing Peptide/metabolism , Gene Expression Regulation , Genes, Immediate-Early , HEK293 Cells , Humans , Intracellular Space/metabolism , Male , Mice, Inbred C57BL , Receptors, Bombesin/metabolism , Sound , Vasoactive Intestinal Peptide/metabolismABSTRACT
The neural substrates and pathophysiological mechanisms underlying the onset of cognitive and motor deficits in autism spectrum disorders (ASDs) remain unclear. Mutations in ASD-associated SHANK3 in mice (Shank3B-/-) result in the accelerated maturation of corticostriatal circuits during the second and third postnatal weeks. Here, we show that during this period, there is extensive remodeling of the striatal synaptic proteome and a developmental switch in glutamatergic synaptic plasticity induced by cortical hyperactivity in striatal spiny projection neurons (SPNs). Behavioral abnormalities in Shank3B-/- mice emerge during this stage and are ameliorated by normalizing excitatory synapse connectivity in medial striatal regions by the downregulation of PKA activity. These results suggest that the abnormal postnatal development of striatal circuits is implicated in the onset of behavioral deficits in Shank3B-/- mice and that modulation of postsynaptic PKA activity can be used to regulate corticostriatal drive in developing SPNs of mouse models of ASDs and other neurodevelopmental disorders.
Subject(s)
Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/metabolism , Behavior, Animal , Corpus Striatum/metabolism , Microfilament Proteins/deficiency , Nerve Tissue Proteins/deficiency , Neurons/metabolism , Animals , Autism Spectrum Disorder/pathology , Corpus Striatum/pathology , Cyclic AMP-Dependent Protein Kinases/genetics , Cyclic AMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Mice , Mice, Knockout , Microfilament Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neurons/pathologyABSTRACT
Serum samples from a total of 71 healthy captive birds belonging to 18 species were collected in July of 2008 in Medellin (Colombia) and tested for flaviviruses. Eighteen of 29 samples from American Flamingoes (Phoenicopterus ruber) were positive for West Nile virus (WNV) by reverse transcription-polymerase chain reaction. Selected positive samples were serially passaged and WNV was confirmed by immunofluorescence. Two isolates (524/08, 9835/08) were characterized in vitro and in vivo. Sequence analysis revealed WNV with 16 nucleotide substitutions resulting in six amino acid changes when compared with the NY99 strain. Colombian (COL) viruses were more closely related to Louisiana isolates from 2001. When compared with attenuated strains isolated from Texas, COL isolates differed in their plaque size and temperature sensitivity phenotype. The COL viruses were pathogenic in embryonated chicken eggs and Balb/c mice.
Subject(s)
Bird Diseases/virology , Birds/virology , RNA, Viral/isolation & purification , West Nile Fever/veterinary , West Nile virus/isolation & purification , Animals , Chickens/virology , Colombia , Louisiana , Mice , Mice, Inbred BALB C , Phenotype , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction , Texas , West Nile Fever/genetics , West Nile Fever/virology , West Nile virus/classification , West Nile virus/geneticsABSTRACT
Transgenic mice, although useful for analyses of gene function, can present unanticipated phenotypic manifestations, including behavioral problems, that may not be directly associated with the gene of interest but rather due to the complex interplay inherent in genomes. These unexpected events can present unique insight into gene function, leading to an advantage in some situations, yet in others can confound interpretation and compromise usefulness of the transgenic line. Here we document that short-term supplementation with S-adenosyl methionine (SAM)--a nutriceutical known to regulate neurotransmitter levels, improve working memory, and reduce aggression--reduced handling- and startling-induced seizures that otherwise precluded behavioral analyses in a transgenic line. This effect lasted for at least 1 mo after withdrawal of SAM and allowed mice to be used in standard maze analyses. These findings suggest that short-term administration of a neurotropic nutriceutical may provide a functional rescue for behavioral studies in an otherwise intractable transgenic mouse line as well as improve the welfare of similar lines.
Subject(s)
Dietary Supplements , S-Adenosylmethionine/administration & dosage , Seizures/prevention & control , Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Alzheimer Disease/psychology , Animals , Apolipoprotein E4/genetics , Behavior, Animal/drug effects , Disease Models, Animal , Humans , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Recombinant Proteins/geneticsABSTRACT
OBJECTIVE: This study was part of a larger effort to test the effectiveness of technology transfer approaches related to evidence-based treatment of co-occurring substance abuse and mental health disorders. Specifically, this study examined characteristics of "opinion leaders" as technology transfer agents. METHOD: A network analysis was conducted within four large substance abuse treatment agencies to identify individuals that other counselors sought out for consultation on co-occurring issues. The identified opinion leaders were then compared with other counselors on demographic variables, education and experience, and attitudes and knowledge about working with individuals with co-occurring disorders. RESULTS: The analyses demonstrate that opinion leaders differed from other counselors in competency-related characteristics including more postgraduate education, relevant professional credentials, and years of experience in mental health treatment. They also had greater knowledge of the dynamics and treatment of co-occurring disorders as well as a greater willingness and confidence in working with such clients. CONCLUSION: These results suggest that opinion leaders are used within agencies for information and consultation regarding treatment issues. Therefore, opinion leaders may provide an important vehicle for dissemination and adoption of evidence-based treatment practices in community treatment settings.