Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189.

Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression, and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1).

Enrichment of GABAA Receptor α-Subunits on the Axonal Initial Segment Shows Regional Differences.

Although it is generally recognized that certain α-subunits of γ-aminobutyric acid type A receptors (GABAARs) form enriched clusters on the axonal initial segment (AIS), the degree to which these clusters vary in different brain areas is not well known. In the current study, we quantified the density, size, and enrichment ratio of fluorescently labeled α1-, α2-, or α3-subunits aggregates co-localized with the AIS-marker ankyrin G and compared them to aggregates in non-AIS locations among different brain areas including hippocampal subfields, basal lateral amygdala (BLA), prefrontal cortex (PFC), and sensory cortex (CTX). We found regional differences in the enrichment of GABAAR α-subunits on the AIS.

Modulation of anxiety and fear via distinct intrahippocampal circuits.

Recent findings indicate a high level of specialization at the level of microcircuits and cell populations within brain structures with regards to the control of fear and anxiety. The hippocampus, however, has been treated as a unitary structure in anxiety and fear research despite mounting evidence that different hippocampal subregions have specialized roles in other cognitive domains. Using novel cell-type- and region-specific conditional knockouts of the GABAA receptor α2 subunit, we demonstrate that inhibition of the principal neurons of the dentate gyrus or CA3 via α2-containing GABAA receptors (α2GABAARs) is required to suppress anxiety, while the inhibition of CA1 pyramidal neurons is required to suppress fear responses.

Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions.

Alcoholism, stress, and anxiety are strongly interacting heritable, polygenetic traits. In a previous study, we identified a quantitative trait locus (QTL) on murine chromosome (Chr) 1 between 23.0 and 31.

Lack of neuronal nitric oxide synthase results in attention deficit hyperactivity disorder-like behaviors in mice.

Nitric oxide (NO) is an important molecule for the proper development and function of the central nervous system. In this study, we investigated the behavioral alterations in the neuronal NO synthase knockout mice (NOS1 KO) with a deficient NO production mechanism in the brain, characterizing it as a potential rodent model for attention deficit hyperactivity disorder (ADHD). NOS1 KO exhibited higher locomotor activity than their wildtype counterparts in a novel environment, as measured by open field (OF) test.

Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189.

We have developed a focal blast model of closed-head mild traumatic brain injury (TBI) in mice. As true for individuals that have experienced mild TBI, mice subjected to 50-60 psi blast show motor, visual and emotional deficits, diffuse axonal injury and microglial activation, but no overt neuron loss. Because microglial activation can worsen brain damage after a concussive event and because microglia can be modulated by their cannabinoid type 2 receptors (CB2), we evaluated the effectiveness of the novel CB2 receptor inverse agonist SMM-189 in altering microglial activation and mitigating deficits after mild TBI.

The behavioral pharmacology of zolpidem: evidence for the functional significance of α1-containing GABA(A) receptors.

Rationale: Zolpidem is a positive allosteric modulator of γ-aminobutyric acid (GABA) with preferential binding affinity and efficacy for α1-subunit containing GABA(A) receptors (α1-GABA(A)Rs). Over the last three decades, a variety of animal models and experimental procedures have been used in an attempt to relate the behavioral profile of zolpidem and classic benzodiazepines (BZs) to their interaction with α1-GABA(A)Rs.

Objectives: This paper reviews the results of rodent and non-human primate studies that have evaluated the effects of zolpidem on motor behaviors, anxiety, memory, food and fluid intake, and electroencephalogram (EEG) sleep patterns.

The effects of repeated zolpidem treatment on tolerance, withdrawal-like symptoms, and GABAA receptor mRNAs profile expression in mice: comparison with diazepam.

Rationale: Zolpidem is a short-acting, non-benzodiazepine hypnotic that acts as a full agonist at α1-containing GABAA receptors. Overall, zolpidem purportedly has fewer instances of abuse and dependence than traditionally used benzodiazepines. However, several studies have shown that zolpidem may be more similar to benzodiazepines in terms of behavioral tolerance and withdrawal symptoms.

Hsp90 chaperone inhibitor 17-AAG attenuates Aβ-induced synaptic toxicity and memory impairment.

The excessive accumulation of soluble amyloid peptides (Aβ) plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in synaptic dysfunction. The role of the two major chaperone proteins, Hsp70 and Hsp90, in clearing misfolded protein aggregates has been established. Despite their abundant presence in synapses, the role of these chaperones in synapses remains elusive.

BDNF deletion or TrkB impairment in amygdala inhibits both appetitive and aversive learning.

Brain-derived neurotrophic factor (BDNF) is known to have an integral role in establishing stable memories after learning events. The neuroplasticity induced by Pavlovian fear conditioning has likewise been shown to rely on interactions between BDNF and its principal receptor, tyrosine kinase receptor B (TrkB), in the amygdala after training. Although the necessity of amygdala bdnf expression and TrkB activation for associative learning within aversive contexts has been explored, it is unclear to what extent this interaction is involved in appetitive learning.

A novel closed-head model of mild traumatic brain injury caused by primary overpressure blast to the cranium produces sustained emotional deficits in mice.

Emotional disorders are a common outcome from mild traumatic brain injury (TBI) in humans, but their pathophysiological basis is poorly understood. We have developed a mouse model of closed-head blast injury using an air pressure wave delivered to a small area on one side of the cranium, to create mild TBI. We found that 20-psi blasts in 3-month-old C57BL/6 male mice yielded no obvious behavioral or histological evidence of brain injury, while 25-40 psi blasts produced transient anxiety in an open field arena but little histological evidence of brain damage.

Potentiation of GluN2C/D NMDA receptor subtypes in the amygdala facilitates the retention of fear and extinction learning in mice.

NMDA receptors are glutamate receptor ion channels that contribute to synaptic plasticity and are important for many forms of learning and memory. In the amygdala, NMDA receptors are critical for the acquisition, retention, and extinction of classically conditioned fear responses. Although the GluN2B subunit has been implicated in both the acquisition and extinction of conditioned fear, GluN2C-knockout mice show reduced conditioned fear responses.

Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization.

Experience-induced changes associated with odor learning are mediated by a number of signaling molecules, including nitric oxide (NO), which is predominantly synthesized by neuronal nitric oxide synthase (nNOS) in the brain. In the current study, we investigated the role of nNOS in the acquisition and retention of conditioned olfactory fear. Mice lacking nNOS received six training trials, each consisting of an odor-CS co-terminating with a foot shock-US.

Targeted entry via somatostatin receptors using a novel modified retrovirus glycoprotein that delivers genes at levels comparable to those of wild-type viral glycoproteins.

Here we report a novel viral glycoprotein created by replacing a natural receptor-binding sequence of the ecotropic Moloney murine leukemia virus envelope glycoprotein with the peptide ligand somatostatin. This new chimeric glycoprotein, which has been named the Sst receptor binding site (Sst-RBS), gives targeted transduction based on three criteria: (i) a gain of the use of a new entry receptor not used by any known virus; (ii) targeted entry at levels comparable to gene delivery by wild-type ecotropic Moloney murine leukemia virus and vesicular stomatitis virus (VSV) G glycoproteins; and (iii) a loss of the use of the natural ecotropic virus receptor. Retroviral vectors coated with Sst-RBS gained the ability to bind and transduce human 293 cells expressing somatostatin receptors.

Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning.

Objective: Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo. However, 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intraperitoneal administration. The authors combined pharmacological, biochemical, and behavioral approaches in a preclinical study examining the role of 7,8-DHF in modulating emotional memory in mice.

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory.

Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus.

Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice.

The heterogeneity and distribution of GABA(A) receptor subunits mediates differential roles in behavior. It is thought that particular behavioral responses to benzodiazepine (BZ) ligands might be associated with an action at a regionally defined receptor subtype. However, the role of specific GABA(A) receptor subtypes in particular brain regions is less clear.

The Use of Lentiviral Vectors and Cre/loxP to Investigate the Function of Genes in Complex Behaviors.

The use of conventional knockout technologies has proved valuable for understanding the role of key genes and proteins in development, disease states, and complex behaviors. However, these strategies are limited in that they produce broad changes in gene function throughout the neuroaxis and do little to identify the effects of such changes on neural circuits thought to be involved in distinct functions. Because the molecular functions of genes often depend on the specific neuronal circuit in which they are expressed, restricting gene manipulation to specific brain regions and times may be more useful for understanding gene functions.

Anxiolytic-like effects of the neurokinin 1 receptor antagonist GR-205171 in the elevated plus maze and contextual fear-potentiated startle model of anxiety in gerbils.

Gerbils show a neurokinin (NK)1 receptor pharmacological profile, which is similar to that observed in humans, and thus have become a commonly used species to test efficacy of NK1 receptor antagonists. The aim of this study was to determine whether systemic administration of the NK1 receptor antagonist GR-205171 produced anxiolytic-like effects in the elevated plus maze and in a novel contextual conditioned fear test using fear-potentiated startle (FPS). On the elevated plus maze, treatment with GR-205171 at 0, 0.

Training-induced changes in the expression of GABAA-associated genes in the amygdala after the acquisition and extinction of Pavlovian fear.

Previous work suggests the gamma-aminobutyric acid (GABA)ergic system may be dynamically regulated during emotional learning. In the current study we examined training-induced changes in the expression of GABA(A)-related genes and the binding of GABA receptor radioligands in the amygdala after the acquisition and extinction of Pavlovian fear. Using in situ hybridization, we examined the expression pattern changes of mRNAs for GABAergic markers in the lateral, basolateral and central subdivisions of the amygdala in C57Bl/6J mice.

Nogo-A inhibition induces recovery from neglect in rats.

Neglect is a complex human cognitive spatial disorder typically induced by damage to prefrontal or posterior parietal association cortices. Behavioral treatments for neglect rarely generalize outside of the therapeutic context or across tasks within the same therapeutic context. Recovery, when it occurs, is spontaneous over the course of weeks to months, but often it is incomplete.

Localized injections of midazolam into the amygdala and hippocampus induce differential changes in anxiolytic-like motor activity in mice.

Various strains of mice display a reliable increase in motor activity in response to benzodiazepines given at low to moderate doses. This hyperactivity has been described as both an anxiolytic-associated increase in exploratory activity and a nonspecific stimulant effect controlled by central neural mechanisms separate from those involved in the anxiolytic-like effects. The purpose of the current study was to investigate the neural circuitry underlying the hyperactivity effects of benzodiazepines in mice.

Posttraining lesions of the auditory thalamus, but not cortex, disrupt the inhibition of fear conditioned to an auditory stimulus.

The purpose of this study was to examine the effects of lesions within the auditory system in an effort to disrupt the processing of the noise stimulus conditioned to inhibit fear. To accomplish this, three experiments were conducted in which rats were first given feature-negative discrimination training in which a noise was conditioned to inhibit fear to a light that signals danger. Following training, rats were given lesions of the medial geniculate body (MGB), auditory thalamus (ADT), or auditory cortex (CTX).

Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion.

The habenula complex modulates the activity of dopamine and serotonin systems in the brain. An important question remains whether there is a link between habenula dysfunction and monoamine-related disorders, such as schizophrenia. In this study, we describe an interaction between habenula lesions and stress that produces long-lasting effects on behavior.

Olfactory-mediated fear conditioning in mice: simultaneous measurements of fear-potentiated startle and freezing.

This study demonstrates that mice display olfactory-cued fear as measured with both freezing and fear-potentiated startle. Following a preconditioning test to measure any unconditioned responses to odor, mice received 5 pairings of a 10-s odor with a 0.25-s, 0.