In this minireview, we discuss different strategies to dissect genetically the keystones of learning and memory. First, we broadly sketch the neurogenetic analysis of complex traits in mice. We then ...discuss two general strategies to find genes affecting learning and memory: candidate gene studies and whole genome searches. Next, we briefly review more recently developed techniques, such as microarrays and RNA interference. In addition, we focus on gene-environment interactions and endophenotypes. All sections are illustrated with examples from the learning and memory field, including a table summarizing the latest information about genes that have been shown to have effects on learning and memory.
Previous studies have suggested that treatment with antagonists or partial agonists of nicotinic acetylcholine receptors containing the beta 2-subunit ( beta 2* nAChRs) results in antidepressant-like ...effects. In this study, we tested three novel compounds with different affinity and functional efficacy at alpha 4 beta 2* nAChRs, which were synthesized as part of nAChR discovery projects at Pfizer, in the tail-suspension, forced-swim, and novelty-suppressed feeding tests of antidepressant efficacy. All compounds tested reduced immobility in the forced-swim test and one of the compounds also reduced immobility in the tail-suspension test. All the compounds appeared to affect food intake on their own, with two compounds reducing feeding significantly in the home cage, precluding a clear interpretation of the results in the novelty-suppressed feeding test. None of the compounds altered locomotor activity at the doses and time points used here. Therefore, a subset of these compounds has pharmacological and behavioral properties that demonstrate the potential of nicotinic compounds as a treatment of mood disorders. Further development of nicotinic-based antidepressants should focus on increasing nAChR subtype selectivity to obtain consistent antidepressant properties with an acceptable side-effect profile.
J. Neurochem. (2011) 119, 240-250. Abstract The spontaneously hypertensive rat (SHR) is widely used as a model of attention-deficit/hyperactivity disorder (ADHD). Deficits in central nicotinic ...receptors (nAChRs) have been previously observed in SHRs, which is interesting since epidemiological studies have identified an association between smoking and ADHD symptoms in humans. Here, we examine whether nAChR deficits in SHRs compared with Wistar Kyoto rat (WKY) controls are nAChR subtype-specific and whether these deficits correlate with changes at the level of mRNA transcription in specific brain regions. Levels of binding sites (Bmax) and dissociation constants (Kd) for nAChRs were determined from saturation curves of high-affinity 3Hepibatidine- and 3H Methyllycaconitine (MLA) binding to membranes from cortex, striatum, hippocampus and cerebellum. In additional brain regions, nAChRs were examined by autoradiography with 125IA-85380 and 125Iα-bungarotoxin. Levels of mRNA encoding nAChR subunits were measured using quantitative real-time PCR (qPCR). We showed that the number of α4β2 nAChR binding sites is lower globally in the SHR brain compared with WKY in the absence of significant differences in mRNA levels, with the exception of lower α4 mRNA in cerebellum of SHR compared with WKY. Furthermore, nAChR deficits were subtype- specific because no strain difference was found in α7 nAChR binding or α7 mRNA levels. Our results suggest that the lower α4β2 nAChR number in SHR compared with WKY may be a consequence of dysfunctional post-transcriptional regulation of nAChRs. PUBLICATION ABSTRACT
The goal of this study was to investigate the influence of 6 months of chronic alcohol consumption on hippocampal neuroanatomy, notably the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) ...terminal fields, and several behaviors, such as radial-maze learning, intermale aggression and anxiety-like behavior, in three inbred strains of mice (NZB, CBA/H, C57BL/6). Based upon several reports highlighting the toxicity of chronic alcohol exposure on the hippocampus, we expected a general diminution of cognitive abilities, with reduced spatial learning skills, increased aggression and anxiety; and concomitantly, a reduction in the sizes of the IIPMF. Contrary to our hypothesis, we did not find an effect of chronic alcohol exposure, neither an effect per se or in interaction with the genotype. Possible explanations for this unexpected finding include ageing effects and species differences between rats and mice.
Mice of the inbred C57BL/6JNmg substrain carry a mutation decreasing the size of the zinc-rich hippocampal intra- and infrapyramidal mossy fibre (IIPMF) terminal fields. In the present experiment, it ...was investigated whether this neurological mutation has also effects on other characteristics of the brain. No morphological differences were found in two other laminated neural structures, the olfactory bulb, where the accessory granular layer is also rich in zinc terminals, and the cerebellum. However, the mutants had a somewhat inferior performance on a motor function task known to test cerebellar involvement. The present findings confirm that previously found effects of this mutation on different types of behaviour are most probably due to the IIPMF. These substrains provide a powerful tool to localise the gene involved and subsequently investigate the plausible pathways leading from gene to behaviour.
Repeated exposure to nicotine induces adaptive changes in the central nervous system including the mesolimbic dopamine (DA) projections from the ventral tegmental area (VTA) to the nucleus accumbens ...(NAc). These modifications can modulate nicotine reward and reinforcement, but also anxiety and depression-related behaviors. The development of addiction-related phenotypes is known to be modulated by regulation of glutamate receptors, as well as activation of transcription factors including cAMP response element-binding protein (CREB), in the NAc.
We investigated the effects of nicotine pre-exposure on nicotine preference and levels of Glur1/2 and CREB in the mesolimbic system in male mice C57BL/6J and BALB/c inbred mice. We also evaluated locomotor activity, anxiety-like and depression-like behaviors known to be affected by nicotine. There were few behavioral changes in mice subjected to chronic nicotine exposure, but there was a marked regulation of GluR2 in the mesolimbic system. Both treated and non-treated animals showed a significant preference for nicotine when facing a choice with a control solution.
These results suggest that voluntary nicotine drinking induces nicotine preference in mice, but does not alter a number of affective behaviors. In addition, alterations in CREB and GluR1 levels are not sufficient to explain preference for nicotine in a 2-bottle choice paradigm.
Background: Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the beta2 subunit, may be effective in treating patients with major depressive disorder. Using 123 ...I5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of beta2 -subunit-containing nAChRs (beta2 *-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied beta2 *-nAChR binding in postmortem brain samples from depressed subjects. Method: The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one 123 I5-I-A-85380 SPECT scan and an MRI scan. The availability of beta2 *-nAChRs was quantified as VT /fP . Postmortem analysis of beta2 *-nAChR binding was conducted with 123 I5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects. Results: The beta2 *-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, beta2 *-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in beta2 *-nAChR number between groups in the postmortem study. Conclusions: Depressed patients have lower beta2 *-nAChR availability than do healthy subjects. The difference between beta2 *-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine. PUBLICATION ABSTRACT
Persistent β Saricicek, Aybala; Esterlis, Irina; Maloney, Kathleen H ...
American Journal of Psychiatry,
08/2012, Letnik:
169, Številka:
8
Journal Article
Recenzirano
Background:Modulation of nicotinic acetylcholine receptors (nAChRs), specifically those containing the β2 subunit, may be effective in treating patients with major depressive disorder. Using ...123I5-I-A-85380 single photon emission computed tomography (SPECT), the authors studied the availability of β2-subunit-containing nAChRs (β2*-nAChRs) in depressed patients. To understand its molecular basis, the authors also studied β2*-nAChR binding in postmortem brain samples from depressed subjects.
Method:The participants were 23 medication-free, nonsmoking subjects with familial, early-onset depression (eight acutely ill and 15 recovered) and 23 age- and gender-matched nonsmoking comparison subjects. Each received one 123I5-I-A-85380 SPECT scan and an MRI scan. The availability of β2*-nAChRs was quantified as VT/fP. Postmortem analysis of β2*-nAChR binding was conducted with 123I5-I-A-85380 on prefrontal cortex samples from 14 depressed subjects and 14 age-matched comparison subjects.
Results:The β2*-nAChR availability in both the acutely ill and recovered depressed subjects was significantly lower across all brain regions than in the respective comparison subjects, and it was lower in the acutely ill subjects than in those who were recovered. In the depressed patients, β2*-nAChR availability was significantly correlated with lifetime number of depressive episodes, trauma score, and anxiety score. There were no differences in β2*-nAChR number between groups in the postmortem study.
Conclusions:Depressed patients have lower β2*-nAChR availability than do healthy subjects. The difference between β2*-nAChR availability in vivo and in post-mortem samples may be analogous to data with dopaminergic PET ligands and dopamine receptor availability; lower receptor availability for the SPECT ligand could be caused by greater endogenous acetylcholine.