Neurosteroids in learning and memory processes
ABSTRACT The discovery that neurosteroids could be synthesized de novo in the brain independent from the periphery and display neuronal actions led to great enthusiasm for the study of their physiological role. Pharmacological studies suggest that neurosteroids may be involved in several physiological processes, such as learning and memory. This chapter summarizes the effects of the administration of neurosteroids on learning and memory capabilities in rodents and in models of amnesia. We address the central mechanisms involved in mediating the modulation of learning and memory processes by neurosteroids. In this regard, the neurosteroid-modulated neurotransmitter systems, such as gamma-aminobutyric acid type A, N-methyl-D-aspartate, and cholinergic and sigma opioid systems, appear to be potential targets for the rapid memory alteration actions of neurosteroids. Moreover, given that some neurosteroids affect neuronal plasticity, this neuronal change could be involved in the long-term modulation of learning and memory processes. To understand the role of endogeneous neurosteroids in learning and memory processes, we present some physiological studies in rodents and humans. However, the latter do not successfully prove a role of endogenous neurosteroids in age-related memory impairments. Finally, we discuss the relative implication of a given neurosteroid vs its metabolites. For this question, a new approach using the quantitative determination of traces of neurosteroids by mass spectrometry seems to have potential for examining the role of each neurosteroid in discrete brain areas in learning and memory alterations, as observed during aging.
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- "On the other hand, PREGS also acts as a negative allosteric modulator of GABA-A receptor. This makes it able to induce a disinhibition of the cholinergic neurons of the nucleus basalis magnocellularis that project to the hippocampus and cerebral cortex, thus strengthening the molecular substrates that underly cognition (Darnaudéry Q2 et al., 1998; Pallarés et al., 1998; Vallée et al., 2001a; Mayo et al., 2003). "
ABSTRACT: Neurosteroids can alter neuronal excitability interacting with specific neurotransmitter receptors, thus affecting several functions such as cognition and emotionality. In this study we investigated, in adult male rats, the effects of the acute administration of pregnenolone-sulfate (PREGS) (10mg/Kg, s. c.) on cognitive processes using the Can test, a non aversive spatial/visual task which allows the assessment of spatial information-acquisition during the baseline training, and of memory retention in the longitudinal study. Furthermore, on the basis of PREGS pharmacological profile, the modulation of depressive-like behaviour was also evaluated in the forced swim test (FST). Our results indicate that acute PREGS induces: an improvement in spatial orientation-acquisition and in reference memory, during the baseline training; a strengthening effect on reference and working memory during the longitudinal study. A decrease in immobility time in the FST has also been recorded. In conclusion, PREGS exerts enhancing properties on acquisition, consolidation and retrieval of spatial information, probably due of improved hippocampal-dependent memory processes. The additional antidepressant effect observed in the FST can provide further evidence in support of the potential of PREGS as a therapeutic tool for the treatment of cognitive deficits associated with mood disorders.Behavioural processes 07/2013; DOI:10.1016/j.beproc.2013.07.001 · 1.46 Impact Factor
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- "The latter has been shown here to be converted to 3a,5b-THPROG, which is known to potentiate the actions of GABA at the GABA A receptor (Lambert et al. 2001) and which would therefore be expected to be amnestic rather than memory enhancing in the IMM (Clements and Bourne 1996). For DHEA, memory enhancing properties are well documented for several learning paradigms in rodents (reviewed in Vallée et al. 2001; Wolf and Kirschbaum 1999). In the day-old chick, direct injection of DHEA into the IMM enhances memory formation when given 5–15 min pre-or 30-to 60-min post-training but not at 180-min post-training (Johnston and Migues 2001; Migues et al. 2002). "
ABSTRACT: Metabolism of the neuroactive steroids pregnenolone (PREG), progesterone (PROG), dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) was investigated in day-old chick brain following direct injection of the (3)H-labelled compounds into the intermediate medial mesopallium and sampling at times known to be crucial for memory formation in this brain region. (3)H-label from these steroids was cleared rapidly from the brain, decreasing to barely detectable levels within 5 h. Following extraction and fractionation, the (3)H-labelled brain steroids were identified by TLC, coupled with acetylation and/or separation in different solvent systems. PREG and PROG were converted within 10 min mostly to 20beta-dihydropregnenolone (20beta-DHPREG) and 5beta-dihydroprogesterone, respectively. There was no detectable metabolism of DHEA. Label from DHEAS persisted for longer (half-time 18.9 min) than the free steroid but with no detectable metabolism other than a small amount (4%) of desulphation to DHEA. Further investigation of chick brain steroid metabolism by incubation of subcellular fractions (1-3 h, 37 degrees C) with PREG, PROG or DHEA plus NADPH led to the formation of the following compounds: 20beta-DHPREG from PREG (particularly in cytosol); 5beta-dihydroprogesterone and 3alpha,5beta-tetrahydroprogesterone from PROG and no detectable metabolism of DHEA. Following incubation of the same brain fractions and labelled steroids with NAD(+), there was no detectable metabolism of PREG or PROG but some conversion of DHEA to androstenedione, especially in the nuclear fraction. The results suggest direct actions of DHEA(S) on the early stages of memory formation in the chick and introduce the possibility that PREG may act indirectly via 20beta-DHPREG.Journal of Neurochemistry 03/2009; 109(2):348-59. DOI:10.1111/j.1471-4159.2009.05965.x · 4.24 Impact Factor
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- "Over the past decade, the identification of the steroids found in the brains of many species has demonstrated a remarkable similarity. Functions associated with these neuroactive compounds has also been identified (reviewed in (Backstrom, et al., 2003,Barbaccia, 2004,Belelli, et al., 2006,Belelli and Lambert, 2005,Bernardi, et al., 2004,Brinton and Wang, 2006,Compagnone and Mellon, 2000,Finn, et al., 2004,Guarneri, et al., 2003,Lambert, et al., 2003,Mensah-Nyagan, et al., 2001,Morrow, et al., 2001,Reddy, 2002,Reddy, 2004,Rogawski and Reddy, 2002,Rupprecht and Holsboer, 1999,Schumacher, et al., 2004,Schumacher, et al., 2003,Stoffel-Wagner, 2003,Tsutsui and Mellon, 2006,Tsutsui, et al., 2004,Uzunova, et al., 2005,Vallee, et al., 2001). However, it is still unknown if these compounds are essential for life. "
ABSTRACT: The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann-Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3beta HSD, as well as those that expressed 3alpha HSD and 5alpha reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of life span, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA(A) receptors may play a role. We treated NP-C mice with a synthetic GABA(A) neurosteroid, ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA(A) receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X-receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.Brain Research Reviews 04/2008; 57(2):410-20. DOI:10.1016/j.brainresrev.2007.05.012 · 5.93 Impact Factor