DHEA action is mediated by multiple receptors and metabolites.

Dehydroepiandrosterone (DHEA) is a C-19 adrenal steroid and the most abundant circulating hormone in humans. Since circulating levels decline in late adulthood, treatment of humans with DHEA has been suggested to have beneficial health effects. Although the mechanism of action is unknown, DHEA may be metabolized to active metabolites that exert their physiological effects by receptor-mediated processes and cell signaling pathways. The purpose of this study was to investigate the mechanistic processes of DHEA action. Since DHEA may exert its pleotropic effects by being metabolized to biologically active species, a GC/MS method was developed to quantify the liver microsomal metabolism of DHEA of various species and identify the P450 enzymes responsible for metabolism. 16alpha-hydroxy-DHEA and 7alpha-hydroxy-DHEA were formed in rat, hamster, pig and human. CYP3A4 and CYP3A5 formed 7alpha-hydroxy-DHEA, 16alpha-hydroxy-DHEA, and the unique human metabolite, 7beta-hydroxy-DHEA, while the fetal enzyme CYP3A7 formed only 16alpha-hydroxy and 7beta-hydroxy-DHEA. By using this method to examine the metabolite profiles of various P450s, the developmental expression patterns of the human cytochrome P4503A forms could be classified and therefore have significant clinical relevance. Nuclear receptors transduce the effects of hormones into transcriptional responses. DHEA and metabolites were screened in a cell-based assay to determine the interaction with estrogen receptors alpha and beta (ERalpha and ERbeta). DHEA, DHEA-S, and androstendiol activated ERalpha, while DHEA, 7-oxo-DHEA, androstenedione and androstenediol activated ERbeta demonstrating ER is activated directly by DHEA and some metabolites. These and other studies from our laboratory demonstrate that DHEA is metabolized into various monohydroxylated metabolites. DHEA and metabolites directly activate ER as well as the pregnane X receptor (PXR). Additionally, DHEA has been shown to activate another nuclear receptor, peroxisome proliferator activated receptor alpha (PPARalpha) in vivo. This research suggests that DHEA action is mediated by multiple receptors and metabolites with various biological activities, comprising of a complex mode of action of DHEA

Temporally Graded Activation of Neocortical Regions in Response to Memories of Different Ages

The temporally graded memory impairment seen in many neurobehavioral disorders implies different neuroanatomical pathways and/or cognitive mechanisms involved in storage and retrieval of memories of different ages. A dynamic interaction between medial-temporal and neocortical brain regions has been proposed to account for memory\u27s greater permanence with time. Despite considerable debate concerning its time-dependent role in memory retrieval, medial-temporal lobe activity has been well studied. However, the relative participation of neocortical regions in recent and remote memory retrieval has received much less attention. Using functional magnetic resonance imaging, we demonstrate robust, temporally graded signal differences in posterior cingulate, right middle frontal, right fusiform, and left middle temporal regions in healthy older adults during famous name identification from two disparate time epochs. Importantly, no neocortical regions demonstrated greater response to older than to recent stimuli. Our results suggest a possible role of these neocortical regions in temporally dating items in memory and in establishing and maintaining memory traces throughout the lifespan. Theoretical implications of these findings for the two dominant models of remote memory functioning (Consolidation Theory and Multiple Trace Theory) are discussed

Age-Related Functional Recruitment for Famous Name Recognition: An Event-Related fMRI Study

Recent neuroimaging research shows that older adults exhibit recruitment, or increased activation on various cognitive tasks. The current study evaluated whether a similar pattern also occurs in semantic memory by evaluating age-related differences during recognition of Recent (since the 1990s) and Enduring (1950s to present) famous names. Fifteen healthy older and 15 healthy younger adults performed the name recognition task with a high and comparable degree of accuracy, although older adults had slower reaction time in response to Recent famous names. Event-related functional MRI showed extensive networks of activation in the two groups including posterior cingulate, right hippocampus, temporal lobe and left prefrontal regions. The Recent condition produced more extensive activation than the Enduring condition. Older adults had more extensive and greater magnitude of activation in 15 of 20 regions, particularly for the Recent condition (15 of 15; 7 of 15 also differed for Enduring); young adults did not show greater activation magnitude in any region. There were no group differences for non-famous names, indicating that age differences are task-specific. The results support and extend the existing literature to semantic memory tasks, indicating that older adult brains use functional recruitment to support task performance, even when task performance accuracy is high

Medial Temporal Lobe Activity for Recognition of Recent and Remote Famous Names: an Event-Related fMRI Study

Previous neuroimaging studies examining recognition of famous faces have identified activation of an extensive bilateral neural network [Gorno Tempini, M. L., Price, C. J., Josephs, O., Vandenberghe, R., Cappa, S. F., Kapur, N. et al. (1998). The neural systems sustaining face and proper-name processing. Brain, 121, 2103–2118], including the medial temporal lobe (MTL) and specifically the hippocampal complex [Haist, F., Bowden, G. J., & Mao, H. (2001). Consolidation of human memory over decades revealed by functional magnetic resonance imaging. Nature Neuroscience, 4, 1139–1145; Leveroni, C. L., Seidenberg, M., Mayer, A. R., Mead, L. A., Binder, J. R., & Rao, S. M. (2000). Neural systems underlying the recognition of familiar and newly learned faces. Journal of Neuroscience, 20, 878–886]. One model of hippocampal functioning in autobiographical, episodic memory retrieval argues that the hippocampal complex remains active in retrieval tasks regardless of time or age of memory (multiple trace theory, MTT), whereas another proposal posits that the hippocampal complex plays a time-limited role in retrieval of autobiographical memories. The current event-related fMRI study focused on the medial temporal lobe and its response to recognition judgments of famous names from two distinct time epochs (1990s and 1950s) in 15 right-handed healthy older adults (mean age = 70 years). A pilot study with an independent sample of young and older subjects ensured that the stimuli were representative of a recent and remote time period. Increased MR signal activity was observed on a bilateral basis for both the hippocampus and parahippocampal gyrus (PHG) during recognition of familiar names from both the recent and remote time periods when compared to non-famous names. However, the impulse response functions in the right hippocampus and right PHG demonstrated a differential response to stimuli from different time epochs, with the 1990s names showing the greatest MR signal intensity change, followed by the 1950s names, followed by foils. The finding that recognition of famous names produced significant bilateral MTL activation regardless of time epoch relative to foils provides support for the MTT model. However, the finding of a temporal gradient in the right MTL also provides support for the HC model, given the greater MTL response associated with recently famous names relative to remotely famous names

Epithelial Overexpression of BDNF or NT4 Disrupts Targeting of Taste Neurons That Innervate the Anterior Tongue

AbstractBrain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4) are essential for the survival of geniculate ganglion neurons, which provide the sensory afferents for taste buds of the anterior tongue and palate. To determine how these target-derived growth factors regulate gustatory development, the taste system was examined in transgenic mice that overexpress BDNF (BDNF-OE) or NT4 (NT4-OE) in basal epithelial cells of the tongue. Overexpression of BDNF or NT4 caused a 93 and 140% increase, respectively, in the number of geniculate ganglion neurons. Surprisingly, both transgenic lines had severe reduction in fungiform papillae and taste bud number, primarily in the dorsal midregion and ventral tip of the tongue. No alterations were observed in taste buds of circumvallate or incisal papillae. Fungiform papillae were initially present on tongues of newborn BDNF-OE animals, but many were small, poorly innervated, and lost postnatally. To explain the loss of nerve innervation to fungiform papillae, the facial nerve of developing animals was labeled with the lipophilic tracer DiI. In contrast to control mice, in which taste neurons innervated only fungiform papillae, taste neurons in BDNF-OE and NT4-OE mice innervated few fungiform papillae. Instead, some fibers approached but did not penetrate the epithelium and aberrant innervation to filiform papillae was observed. In addition, some papillae that formed in transgenic mice had two taste buds (instead of one) and were frequently arranged in clusters of two or three papillae. These results indicate that target-derived BDNF and NT4 are not only survival factors for geniculate ganglion neurons, but also have important roles in regulating the development and spatial patterning of fungiform papilla and targeting of taste neurons to these sensory structures

Winter 1979

Clubhouse Plants (page 3) Massachusetts Pesticide News (6) The Alsea Report on 2,4,5-T (8) Better Pest Control (10) Acid Rain: Something Else to Worry About? (11) UMass Turfgrass Research Update (13) 1979 Preemergence Crabgrass Control Tria