An Biomarker to Characterize Ototoxic Compounds and Novel Protective Therapeutics.

There are no approved therapeutics for the prevention of hearing loss and vestibular dysfunction from drugs like aminoglycoside antibiotics. While the mechanisms underlying aminoglycoside ototoxicity remain unresolved, there is considerable evidence that aminoglycosides enter inner ear mechanosensory hair cells through the mechanoelectrical transduction (MET) channel. Inhibition of MET-dependent uptake with small molecules or modified aminoglycosides is a promising otoprotective strategy.

ORC-13661 protects sensory hair cells from aminoglycoside and cisplatin ototoxicity.

Aminoglycoside (AG) antibiotics are widely used to prevent life-threatening infections, and cisplatin is used in the treatment of various cancers, but both are ototoxic and result in loss of sensory hair cells from the inner ear. ORC-13661 is a new drug that was derived from PROTO-1, a compound first identified as protective in a large-scale screen utilizing hair cells in the lateral line organs of zebrafish larvae. Here, we demonstrate, in zebrafish larvae and in mouse cochlear cultures, that ORC-13661 provides robust protection of hair cells against both ototoxins, the AGs and cisplatin.

A role for the lateral dorsal tegmentum in memory and decision neural circuitry.

A role for the hippocampus in memory is clear, although the mechanism for its contribution remains a matter of debate. Converging evidence suggests that hippocampus evaluates the extent to which context-defining features of events occur as expected. The consequence of mismatches, or prediction error, signals from hippocampus is discussed in terms of its impact on neural circuitry that evaluates the significance of prediction errors: Ventral tegmental area (VTA) dopamine cells burst fire to rewards or cues that predict rewards (Schultz, Dayan, & Montague, 1997).

The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder.

Background: Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder precipitated by exposure to extreme traumatic stress. Yet, most individuals exposed to traumatic stress do not develop PTSD and may be considered psychologically resilient. The neural circuits involved in susceptibility or resiliency to PTSD remain unclear, but clinical evidence implicates changes in the noradrenergic system.

5-HT(2A) receptor mediated neuronal activation within the paraventricular nucleus of the hypothalamus is desensitized following prolonged glucocorticoid treatment.

An organism's ability to adapt successfully to stress reflects an equilibrium that requires not only an appropriate response, but also an ability to control that response. The hypothalamic-pituitary-adrenal (HPA) axis contributes to these homeostatic actions. Previous research implicates involvement of the serotonergic 5-HT(2A) receptors of the hypothalamic paraventricular nucleus (PVN) in HPA axis activation.

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system.

Introduction: Prior activation of the kappa opioid system by repeated stress or agonist administration has been previously shown to potentiate the rewarding properties of subsequently administered cocaine. In the present study, intermittent and uncontrollable footshock, a single session of forced swim, or acute administration of the kappa agonist U50,488 (5 mg/kg) were found to reinstate place preference in mice previously conditioned with cocaine (15 mg/kg) and subsequently extinguished by repeated training sessions without drug.

Results And Discussion: Stress-induced reinstatement did not occur for mice pretreated with the kappa opioid receptor antagonist norbinaltorphimine (10 mg/kg) and did not occur in mice lacking either kappa opioid receptors (KOR -/-) or prodynorphin (Dyn -/-).

Hippocampal cell proliferation is reduced following prenatal ethanol exposure but can be rescued with voluntary exercise.

The ingestion of ethanol during pregnancy has a number of deleterious consequences for the unborn offspring, producing structural and functional deficits that affect the brain and many other organs into adulthood. The hippocampus is a brain area that is particularly sensitive to ethanol's adverse effects. In a previous study we showed that voluntary exercise can ameliorate deficits in long-term potentiation and behavior that occur following prenatal ethanol exposure (Eur J Neurosci, 2005, 21, 1719-1726).

Voluntary exercise rescues deficits in spatial memory and long-term potentiation in prenatal ethanol-exposed male rats.

Prenatal ethanol exposure can lead to long-lasting impairments in the ability to process spatial information in rats, as well as produce long-lasting deficits in the ability of animals to exhibit long-term potentiation, a biological model of learning and memory processing. Conversely, we have recently shown that both spatial memory and long-term potentiation can be enhanced in animals that are given access to a running wheel in their home cage. In the present study, Sprague-Dawley rat dams were given one of three diets throughout gestation: (i) a liquid diet containing ethanol (35.

Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density.

Voluntary exercise produces a dramatic increase in the number of bromodeoxyuridine (BrdU)-positive cells in the adult dentate gyrus (DG); however, it has never been determined whether this increase reflects neurogenic activity or some exercise-induced change in the metabolic processing of systemically injected BrdU. In these experiments, we show that 1) 200 mg/kg is a saturating dose for single injections of BrdU in both control and voluntary exercise animals; 2) there is significantly more cell labeling in animals that exercise when saturating doses of BrdU are employed; 3) high doses of BrdU do not affect the number, appearance, or distribution of labeled cells; 4) voluntary exercise leads to similar increases in the number of cells expressing Ki67, an intrinsic marker of cellular proliferation; 5) both dendritic length and complexity are significantly increased in the DG of animals that exercise; and 6) spine density is significantly greater on dendrites in the DG following voluntary exercise. This study demonstrates that exercise up-regulates neurogenic activity in the DG of adult rats, independently of any putative changes in altered BrdU metabolism, and that it also substantially alters the morphology of dentate granule cell dendrites.