The molecular mechanisms controlling the oscillatory synthesis of melatonin in rat pineal gland involve the rhythmic expression of several genes including arylalkylamine N -acetyltransferase ( AA-NAT ), inducible cAMP early repressor ( ICER ), and Fos-related antigen-2 ( fra-2 ). Here we show that the calcium sensors downstream regulatory element antagonist modulator/potassium channel interacting protein (DREAM/KChIP)-3 and KChIP-1, -2 and -4 bind to downstream regulatory element (DRE) sites located in the regulatory regions of these genes and repress basal and induced transcription from ICER, fra-2 or AA-NAT promoters. Importantly, we demonstrate that the endogenous binding activity to DRE sites shows day-night oscillations in rat pineal gland and retina but not in the cerebellum. The peak of DRE binding activity occurs during the day period of the circadian cycle, coinciding with the lowest levels of fra-2, ICER , and AA-NAT transcripts. We show that a rapid clearance of DRE binding activity during the e...

While increasing evidence demonstrates a role for enhanced dopamine transmission in cocaine priming-induced reinstatement of drug seeking, the circuitry mediating drug seeking has not been fully described. The goal of these experiments is to further elucidate the role of mesoaccumbal dopaminergic pathways in the reinstatement of cocaine-seeking behavior. Initially, rats were trained to press a lever for cocaine (0.254 mg/60 ?l, i.v.) using a fixed-ratio five (FR5) schedule of reinforcement. Responding then was extinguished by substituting saline for cocaine. Following extinction, the ability of a systemically administered dopamine transporter blocker, GBR 12909, to induce reinstatement of cocaine seeking was assessed. A priming injection of GBR 12909 (10 mg/kg, i.p.) reinstated drug-seeking behavior to levels of responding that were not statistically different from those produced by a cocaine prime (10 mg/kg, i.p.), which confirms that increased dopaminergic transmission plays a critical role in priming-in...

Background and Purpose: Rapid and complete tissue reoxygenation is a prime goal of present stroke therapy. However, reoxygenation may trigger detrimental cascades that partly antagonize beneficial effects. It was the goal to investigate selective grading of reoxygenation with targeting of single mitochondrial complexes in murine hippocampal slices. Methods: Population spike amplitude (PSAP) and NADH were measured during hypoxic hypoxia and recovery thereof. With onset of reoxygenation slices were treated for different times with amobarbital (1 mM), malonate (2 mM), or cyanide (1 mM), inhibitors of mitochondrial complex I, II, or IV, respectively. Other slices were treated with nicotinamide (1 mM). Results: Posthypoxic recovery of PSAP increased from 32 ± 43 % of onset in control slices to 52 ± 59 % (p < 0.05) upon treatment with amobarbital for 1 minute and 62 ± 37 % (p < 0.05) upon treatment with malonate. With nicotinamide posthypoxic recovery improved up to 73 ± 25 % (p < 0.05). Oxidation of NADH was pr...

Immunization against beta-amyloid can reduce neuropathology and improve impaired behavior in transgenic mice. Whether antibodies against beta-amyloid are also effective in Alzheimer disease (AD) is unknown. We have previously described the generation of antibodies against beta-amyloid in AD patients who received a prime and a booster immunization of aggregated Abeta42 in a placebo-controlled randomized trial. We developed a tissue amyloid plaque immunoreactivity (TAPIR) assay to determine the ability of the antibodies to react with bona fide beta-amyloid plaques in brain tissue of transgenic mice expressing AD-causing mutations. By following patients over a one-year period, we found that patients who generated TAPIR-positive antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, and scored better on hippocampus-dependent memory tests as compared to patients without such antibodies. The beneficial clinical effects were also present in patients who had ...

It is widely accepted that holistic processing is critical for early face recognition, but recent work has suggested a larger role for feature-based processing. Indeed, there is some indication that as familiarity increases, recognition becomes less dep...

Circadian rhythms are biological processes that cycle across 24 h and regulate many facets of neurophysiology, including learning and memory. Circadian variation in spatial memory task performance is well documented; however, the effect of sex across circadian time (CT) remains unclear. Additionally, little is known regarding the impact of time-of-day on hippocampal neuronal physiology. Here, we investigated the influence of both sex and time-of-day on hippocampal neurophysiology and memory in mice. Performance on the object location memory (OLM) task depended on both circadian time and sex, with memory enhanced at night in males but during the day in females. Long-term synaptic potentiation (LTP) magnitude at CA3-CA1 synapses was greater at night compared with day in both sexes. Next, we measured spontaneous synaptic excitation and inhibition onto CA1 pyramidal neurons. Frequency and amplitude of inhibition was greater during the day compared with night, regardless of sex. Frequency and amplitude of excit...

The Cre-lox system is an indispensable tool in neuroscience research for targeting gene deletions to specific cellular populations. Here we assess the utility of several transgenic Cre lines, along with a viral approach, for targeting cerebellar Purkinje cells (PCs) in mice. Using a combination of a fluorescent reporter line ( Ai14 ) to indicate Cre -mediated recombination and a floxed Dystroglycan line ( Dag1flox ), we show that reporter expression does not always align precisely with loss of protein. The commonly used Pcp2Cre line exhibits a gradual mosaic pattern of Cre recombination in PCs from Postnatal Day 7 (P7) to P14, while loss of Dag1 protein is not complete until P30. Ptf1aCre drives recombination in precursor cells that give rise to GABAergic neurons in the embryonic cerebellum, including PCs and molecular layer interneurons. However, due to its transient expression in precursors, Ptf1aCre results in stochastic loss of Dag1 protein in these neurons. NestinCre , which is often described as a “p...

Hot flushes are generally a consequence of declining sex steroid hormone levels and a prime reason why menopausal women seek medical treatment. A hot flush generally lasts several minutes and consists of a warming sensation in the chest and face accompanied by sweating, vasodilation (flushing) and in some instances, feelings of nausea and illness. Currently, estrogens and/or some progestins are the most effective therapeutics for the treatment of hot flushes. Although steroid hormone treatments are a very effective means of alleviating hot flushes, these therapies are not acceptable or indicated for all women. Thus, non-steroid hormonal therapies (e.g. venlafaxine, fluoxetine, paroxetine, clonidine, gabapentin) are being evaluated clinically even though they are less effective than sex steroids. We have modified and developed rat models for vasomotor instability based on measuring tail skin temperature (TST) in ovariectomized (OVX) rats. The first model includes modification and optimization of the classic...

Modern spatial navigation requires fluency with multiple representational formats, including visual scenes, signs, and words. These formats convey different information. Visual scenes are rich and specific but contain extraneous details. Arrows, as an example of signs, are schematic representations in which the extraneous details are eliminated, but analog spatial properties are preserved. Words eliminate all spatial information and convey spatial directions in a purely abstract form. How does the human brain compute spatial directions within and across these formats? To investigate this question, we conducted two experiments on men and women: a behavioral study that was preregistered and a neuroimaging study using multivoxel pattern analysis of fMRI data to uncover similarities and differences among representational formats. Participants in the behavioral study viewed spatial directions presented as images, schemas, or words (e.g., “left”), and responded to each trial, indicating whether the spatial direc...

Visual context plays a prominent role in every day perception. Contextual information can facilitate recognition of objects within scenes by providing predictions about objects that are most likely to appear in a specific setting, along with the locatio...