Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following flurothyl-induced seizures: A dissociation of hippocampal Fos from seizure activity.

Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final flurothyl rechallenge.

Perinatal vs genetic programming of serotonin states associated with anxiety.

Large numbers of women undergo antidepressant treatment during pregnancy; however, long-term consequences for their offspring remain largely unknown. Rodents exposed to serotonin transporter (SERT)-inhibiting antidepressants during development show changes in adult emotion-like behavior. These changes have been equated with behavioral alterations arising from genetic reductions in SERT.

Increased antidepressant sensitivity after prefrontal cortex glucocorticoid receptor gene deletion in mice.

Our laboratory has previously shown that antidepressants regulate glucocorticoid receptor (GR) expression in the prefrontal cortex (PFC). To determine if PFC GR are involved in antidepressant effects on behavior or hypothalamic-pituitary-adrenocortical (HPA) axis activity, we treated floxed GR male mice with saline or 15 or 30 mg/kg/d imipramine after PFC injection of adeno-associated virus 2/9 vectors transducing expression of Cre recombinase, to knock-down GR (PFC-GRKD), or green fluorescent protein (PFC-GFP), to serve as a control. The pattern of virally transduced GR deletion, common to all imipramine treatment groups, included the infralimbic, prelimbic, and medial anterior cingulate cortex at its largest extent, but was confined to the prelimbic and anterior cingulate cortex at its smallest extent.

Seizure-dependent mTOR activation in 5-HT neurons promotes autism-like behaviors in mice.

Epilepsy and autism spectrum disorder (ASD) are common comorbidities of one another. Despite the prevalent correlation between the two disorders, few studies have been able to elucidate a mechanistic link. We demonstrate that forebrain specific Tsc1 deletion in mice causes epilepsy and autism-like behaviors, concomitant with disruption of 5-HT neurotransmission.

The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke.

The contribution of oxidative stress to ischemic brain damage is well established. Nevertheless, for unknown reasons, several clinically tested antioxidant therapies have failed to show benefits in human stroke. Based on our previous in vitro work, we hypothesized that the neuroprotective potency of antioxidants is related to their ability to limit the release of the excitotoxic amino acids glutamate and aspartate.

Determining the oligomer number of native GPCR using florescence correlation spectroscopy and drug-induced inactivation-reactivation.

GPCRs are a major family of homologous proteins and are key mediators of the effects of numerous endogenous neurotransmitters, hormones, cytokines, therapeutic drugs, and drugs-of-abuse. Despite the enormous amount of research on the pharmacological and biochemical properties of GPCRs, there is surprisingly little information on GPCR dimer structure and function in primary cell culture or in vivo. We have used two novel approaches to develop methods to detect and study GPCR dimer function: FCS/PCH and "inactivation-reactivation".

Place conditioning to apomorphine in rat models of Parkinson's disease: differences by dose and side-effect expression.

One potential complication of treating Parkinson's Disease (PD) with dopaminergic drugs is dopamine dysregulation syndrome, an addiction-like response to the drug therapy. Here, we assessed whether rats given parkinsonian-like symptoms with a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle (6-OHDA-MFB), exhibit similar behavior. To examine this, we injected these rats or sham-lesioned rats subcutaneously (sc) with apomorphine (APO) at low (0.

LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes.

In mammals, cellular swelling activates release of small organic osmolytes, including the excitatory amino acids (EAA) glutamate and aspartate, via a ubiquitously expressed volume-regulated chloride/anion channel (VRAC). Pharmacological evidence suggests that VRAC plays plural physiological and pathological roles, including excitotoxic release of glutamate in stroke. However, the molecular identity of this pathway was unknown.

Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress.

Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls.

Synergistic effects on dopamine cell death in a Drosophila model of chronic toxin exposure.

The neurodegenerative effects of Parkinson's disease (PD) are marked by a selective loss of dopaminergic (DA) neurons. Epidemiological studies suggest that chronic exposure to the pesticide paraquat may increase the risk for PD and DA cell loss. However, combined exposure with additional fungicide(s) including maneb and/or ziram may be required for pathogenesis.

Stimulation of the subthalamic nucleus engages the cerebellum for motor function in parkinsonian rats.

Deep brain stimulation (DBS) is effective in managing motor symptoms of Parkinson's disease in well-selected individuals. Recently, research has shown that DBS in the basal ganglia (BG) can alter neural circuits beyond the traditional basal ganglia-thalamus-cortical (BG-TH-CX) loop. For instance, functional imaging showed alterations in cerebellar activity with DBS in the subthalamic nucleus (STN).

Deficits in neuronal cytochrome P450 activity attenuate opioid analgesia but not opioid side effects.

Morphine-like analgesics act on µ opioid receptors in the CNS to produce highly effective pain relief, but the same class of receptors also mediates non-therapeutic side effects. The analgesic properties of morphine were recently shown to require the activity of a brain neuronal cytochrome P450 epoxygenase, but the significance of this pathway for opioid side effects is unknown. Here we show that brain P450 activity is not required for three of morphine׳s major side effects (respiratory depression, constipation, and locomotor stimulation).

Deep brain stimulation for obsessive-compulsive disorder: systematic review and evidence-based guideline sponsored by the American Society for Stereotactic and Functional Neurosurgery and the Congress of Neurological Surgeons (CNS) and endorsed by the CNS and American Association of Neurological Surgeons.

Background: It is estimated that 40% to 60% of patients with obsessive-compulsive disorder (OCD) continue to experience symptoms despite adequate medical management. For this population of treatment-refractory patients, promising results have been reported with the use of deep brain stimulation (DBS).

Objective: To conduct a systematic review of the literature and develop evidence-based guidelines on DBS for OCD.

Comparison of the efficacy of five adeno-associated virus vectors for transducing dorsal raphé nucleus cells in the mouse.

Background: Delivery of genes to various brain regions can be accomplished using serotype 2 of the adeno-associated virus (AAV). Pseudotype AAV2 vectors, composed of the AAV2 genome packaged in the capsid of an alternative serotype, have increased efficiency of viral transduction. Transduction of pseudotype AAV2 vectors depends on cell type, brain region and stage of development.

Significance of neuronal cytochrome P450 activity in opioid-mediated stress-induced analgesia.

Stressful environmental changes can suppress nociceptive transmission, a phenomenon known as "stress-induced analgesia". Depending on the stressor and the subject, opioid or non-opioid mechanisms are activated. Brain μ opioid receptors mediate analgesia evoked either by exogenous agents (e.

Supraspinal stimulation for treatment of refractory pain.

Refractory pain syndromes often have far reaching effects and are quite a challenge for primary care providers and specialists alike to treat. With the help of site-specific neuromodulation and appropriate patient selection these difficult to treat pain syndromes may be managed. In this article, we focus on supraspinal stimulation (SSS) for treatment of intractable pain and discuss off-label uses of deep brain stimulation (DBS) and motor cortex stimulation (MCS) in context to emerging indications in neuromodulation.

Maternal cigarette smoking during pregnancy predicts drug use via externalizing behavior in two community-based samples of adolescents.

Background And Aims: Prenatal exposure to maternal cigarette smoking (PEMCS) is associated with a higher probability of substance use in adolescence. We explore if externalizing behavior mediates this relationship, while controlling for a number of potential covariates of this mediation process.

Methods: We used data obtained in two geographically distinct community samples of adolescents.

The redistribution of Drosophila vesicular monoamine transporter mutants from synaptic vesicles to large dense-core vesicles impairs amine-dependent behaviors.

Monoamine neurotransmitters are stored in both synaptic vesicles (SVs), which are required for release at the synapse, and large dense-core vesicles (LDCVs), which mediate extrasynaptic release. The contributions of each type of vesicular release to specific behaviors are not known. To address this issue, we generated mutations in the C-terminal trafficking domain of the Drosophila vesicular monoamine transporter (DVMAT), which is required for the vesicular storage of monoamines in both SVs and LDCVs.

Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate.

Filamin B (FlnB) is an actin-binding protein thought to transduce signals from various membrane receptors and intracellular proteins onto the actin cytoskeleton. Formin1 (Fmn1) is an actin-nucleating protein, implicated in actin assembly and intracellular signaling. Human mutations in FLNB cause several skeletal disorders associated with dwarfism and early bone fusion.

Drosophila melanogaster as a genetic model system to study neurotransmitter transporters.

The model genetic organism Drosophila melanogaster, commonly known as the fruit fly, uses many of the same neurotransmitters as mammals and very similar mechanisms of neurotransmitter storage, release and recycling. This system offers a variety of powerful molecular-genetic methods for the study of transporters, many of which would be difficult in mammalian models. We review here progress made using Drosophila to understand the function and regulation of neurotransmitter transporters and discuss future directions for its use.

Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria-like behavior and impairs hypothalamic-pituitary-adrenocortical axis feedback inhibition.

Glucocorticoids can cause depression and anxiety. Mechanisms for glucocorticoid effects on mood are largely undefined. The dorsal raphé nucleus (DRN) produces the majority of serotonin in the brain, and expresses glucocorticoid receptors (GR).

Segregation of seizure traits in C57 black mouse substrains using the repeated-flurothyl model.

Identifying the genetic basis of epilepsy in humans is difficult due to its complexity, thereby underlying the need for preclinical models with specific aspects of seizure susceptibility that are tractable to genetic analyses. In the repeated-flurothyl model, mice are given 8 flurothyl-induced seizures, once per day (the induction phase), followed by a 28-day rest period (incubation phase) and final flurothyl challenge. This paradigm allows for the tracking of multiple phenotypes including: initial generalized seizure threshold, decreases in generalized seizure threshold with repeated flurothyl exposures, and changes in the complexity of seizures over time.

δ-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice.

Background And Purpose: Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ-opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models.

Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward.

μ-opioid receptors (MORs) are necessary for the analgesic and addictive effects of opioids such as morphine, but the MOR-expressing neuronal populations that mediate the distinct opiate effects remain elusive. Here we devised a new conditional bacterial artificial chromosome rescue strategy to show, in mice, that targeted MOR expression in a subpopulation of striatal direct-pathway neurons enriched in the striosome and nucleus accumbens, in an otherwise MOR-null background, restores opiate reward and opiate-induced striatal dopamine release and partially restores motivation to self administer an opiate. However, these mice lack opiate analgesia or withdrawal.