Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.

A Role for PGC-1α in Transcription and Excitability of Neocortical and Hippocampal Excitatory Neurons.

The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a critical regulator of genes involved in neuronal metabolism, neurotransmission, and morphology. Reduced PGC-1α expression has been implicated in several neurological and psychiatric disorders. An understanding of PGC-1α's roles in different cell types will help determine the functional consequences of PGC-1α dysfunction and/or deficiency in disease. Reports from our laboratory and others suggest a critical role for PGC-1α in inhibitory neurons with high metabolic demand such as fast-spiking interneurons. Here, we document a previously unrecognized role for PGC-1α in maintenance of gene expression programs for synchronous neurotransmitter release, structure, and metabolism in neocortical and hippocampal excitatory neurons. Deletion of PGC-1α from these neurons caused ambulatory hyperactivity in response to a novel environment and enhanced glutamatergic transmission in neocortex and hippocampus, along with reductions in mRNA levels from several PGC-1α neuron-specific target genes. Given the potential role for a reduction in PGC-1α expression or activity in Huntington Disease (HD), we compared reductions in transcripts found in the neocortex and hippocampus of these mice to that of an HD knock-in model; few of these transcripts were reduced in this HD model. These data provide novel insight into the function of PGC-1α in glutamatergic neurons and suggest that it is required for the regulation of structural, neurosecretory, and metabolic genes in both glutamatergic neuron and fast-spiking interneuron populations in a region-specific manner. These findings should be considered when inferring the functional relevance of changes in PGC-1α gene expression in the context of disease.

Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells.

Recent evidence suggests that interneurons are involved in the pathophysiology of Huntington Disease (HD). Abnormalities in the function of interneurons expressing the calcium buffer parvalbumin (PV) have been observed in multiple mouse models of HD, although it is not clear how PV-positive interneuron dysfunction contributes to behavioral and synaptic deficits. Here, we use the cre-lox system to drive expression of mutant huntingtin (mthtt) in parvalbumin (PV)-positive neurons and find that mutant mice exhibit diffuse mthtt immunoreactivity in PV-rich areas at 10months of age and mthtt aggregates in PV-positive processes at 24months of age. At midlife, mutant mice are hyperactive and display impaired GABA release in the motor cortex, characterized by reduced miniature inhibitory events and severely blunted responses to gamma frequency stimulation, without a loss of PV-positive interneurons. In contrast, 24month-old mutant mice show normalized behavior and responses to gamma frequency stimulation, possibly due to compensatory changes in pyramidal neurons or the formation of inclusions with age. These data indicate that mthtt expression in PV-positive neurons is sufficient to drive a hyperactive phenotype and suggest that mthtt-mediated dysfunction in PV-positive neuronal populations could be a key factor in the hyperkinetic behavior observed in HD. Further clarification of the roles for specific PV-positive populations in this phenotype is warranted to definitively identify cellular targets for intervention.

A descriptive study of hypertension in Vietnamese Americans.

This study focused on the extent of hypertension (HTN) and risk factors in 201 Vietnamese in a Gulf Coast community. Blood pressure and pulse were measured by a Welch-Allyn Vital Signs Monitor (Model AD-9000, Armstrong Medical, Lincolnshire, IL). The survey tool consisted of demographic information, health status, medications, dietary habits, smoking and alcohol use, education, family configuration, family health history, and 12 true or false items on HTN knowledge. Participants believed that HTN was inherited, presented symptoms, was caused by stress and lack of daily exercise, and had no cure. Of the factors correlated with high blood pressure, the most significant item was the total knowledge score. Nearly 44% of the participants in this sample were hypertensive. Other significant correlation findings included smoking r = .45, p < .05) and exercise r = .15, p < .05) were related to high blood pressure. Cultural sensitivity was found to be critical in the data collection process. This study demonstrates a profound need for health education related to cardiovascular disease, smoking, and alcohol use in Vietnamese Americans.

The effects of a short-term exercise program on movement, pain, and mood in the elderly. Results of a pilot study.

Therapeutic effects of a short-term Tai Chi exercise program for the elderly were evaluated in a pretest-posttest quasi-experimental design. This pilot study evaluated changes in flexibility, balance, sway, pain, and mood after a short slow-motion exercise. The program consisted of a series of movements involving turning, shifting weight, bending, and arm movements in combination with diaphragmatic breathing with slow movements. The measured effects included improved balance, sway, range of motion, decreased perceived pain, and lessened trait anxiety. Participants included 11 elderly females. Instruments consisted of standard goniometry, the Multiple Affect Adjective Check List, stopwatch measures of single-leg stance and a tandem walk (sway), and visual analog measurement of pain. Findings included significant improvement (p = .05) in trait anxiety and pain perception. Improvements in mood, flexibility, and balance may have a profound effect on the incidence of falls, injuries, resulting disability, and overall quality of life.

The clinical nurse researcher in a military setting: bringing practice into research.

The clinical nurse researcher (CNR) is emerging as an integral part of every major medical center. The CNR has six basic roles: facilitate the conduct of research projects; stimulate staff to conduct research: upgrade the research skills of the staff; participate on committees related to research; conduct and disseminate research; and obtain funding for research studies. Readiness issues for military missions, health promotion, and disease management and prevention are consistently of interest. The CNR should be an active participant on the institutional review board and should conduct primary studies that further the reputation of the facility. The viability of any military research program today is contingent on procurement of funding; therefore, the CNR must refine skills in grantsmanship. The demands of the medical facility and the needs of the staff must be a prime consideration in the development of the role of the CNR.