Epigenetic Alterations Are Critical for Fear Memory Consolidation and Synaptic Plasticity in the Lateral Amygdala

Epigenetic mechanisms, including histone acetylation and DNA methylation, have been widely implicated in hippocampal-dependent learning paradigms. Here, we have examined the role of epigenetic alterations in amygdala-dependent auditory Pavlovian fear conditioning and associated synaptic plasticity in the lateral nucleus of the amygdala (LA) in the rat. Using Western blotting, we first show that auditory fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in the LA, and that training-related alterations in histone acetylation and DNMT3A expression in the LA are downstream of ERK/MAPK signaling. Next, we show that intra-LA infusion of the histone deacetylase (HDAC) inhibitor TSA increases H3 acetylation and enhances fear memory consolidation; that is, long-term memory (LTM) is enhanced, while short-term memory (STM) is unaffected. Conversely, intra-LA infusion of the DNA methyltransferase (DNMT) inhibitor 5-AZA impairs fear memory consolidation. Further, intra-LA infusion of 5-AZA was observed to impair training-related increases in H3 acetylation, and pre-treatment with TSA was observed to rescue the memory consolidation deficit induced by 5-AZA. In our final series of experiments, we show that bath application of either 5-AZA or TSA to amygdala slices results in significant impairment or enhancement, respectively, of long-term potentiation (LTP) at both thalamic and cortical inputs to the LA. Further, the deficit in LTP following treatment with 5-AZA was observed to be rescued at both inputs by co-application of TSA. Collectively, these findings provide strong support that histone acetylation and DNA methylation work in concert to regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA

Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics

A major recent discovery was the identification of an expansion of a non-coding GGGGCC hexanucleotide repeat in the C9ORF72 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis. Mutations in two other genes are known to account for familial frontotemporal dementia: microtubule-associated protein tau and progranulin. Although imaging features have been previously reported in subjects with mutations in tau and progranulin, no imaging features have been published in C9ORF72. Furthermore, it remains unknown whether there are differences in atrophy patterns across these mutations, and whether regional differences could help differentiate C9ORF72 from the other two mutations at the single-subject level. We aimed to determine the regional pattern of brain atrophy associated with the C9ORF72 gene mutation, and to determine which regions best differentiate C9ORF72 from subjects with mutations in tau and progranulin, and from sporadic frontotemporal dementia. A total of 76 subjects, including 56 with a clinical diagnosis of behavioural variant frontotemporal dementia and a mutation in one of these genes (19 with C9ORF72 mutations, 25 with tau mutations and 12 with progranulin mutations) and 20 sporadic subjects with behavioural variant frontotemporal dementia (including 50% with amyotrophic lateral sclerosis), with magnetic resonance imaging were included in this study. Voxel-based morphometry was used to assess and compare patterns of grey matter atrophy. Atlas-based parcellation was performed utilizing the automated anatomical labelling atlas and Statistical Parametric Mapping software to compute volumes of 37 regions of interest. Hemispheric asymmetry was calculated. Penalized multinomial logistic regression was utilized to create a prediction model to discriminate among groups using regional volumes and asymmetry score. Principal component analysis assessed for variance within groups. C9ORF72 was associated with symmetric atrophy predominantly involving dorsolateral, medial and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes and cerebellum. In contrast, striking anteromedial temporal atrophy was associated with tau mutations and temporoparietal atrophy was associated with progranulin mutations. The sporadic group was associated with frontal and anterior temporal atrophy. A conservative penalized multinomial logistic regression model identified 14 variables that could accurately classify subjects, including frontal, temporal, parietal, occipital and cerebellum volume. The principal component analysis revealed similar degrees of heterogeneity within all disease groups. Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia. Our analysis suggested that imaging has the potential to be useful to help differentiate C9ORF72 from these other groups at the single-subject level

Food-associated cues alter forebrain functional connectivity as assessed with immediate early gene and proenkephalin expression

<p>Abstract</p> <p>Background</p> <p>Cues predictive of food availability are powerful modulators of appetite as well as food-seeking and ingestive behaviors. The neurobiological underpinnings of these conditioned responses are not well understood. Monitoring regional immediate early gene expression is a method used to assess alterations in neuronal metabolism resulting from upstream intracellular and extracellular signaling. Furthermore, assessing the expression of multiple immediate early genes offers a window onto the possible sequelae of exposure to food cues, since the function of each gene differs. We used immediate early gene and proenkephalin expression as a means of assessing food cue-elicited regional activation and alterations in functional connectivity within the forebrain.</p> <p>Results</p> <p>Contextual cues associated with palatable food elicited conditioned motor activation and corticosterone release in rats. This motivational state was associated with increased transcription of the activity-regulated genes <it>homer1a</it>, <it>arc</it>, <it>zif268</it>, <it>ngfi-b </it>and c-<it>fos </it>in corticolimbic, thalamic and hypothalamic areas and of proenkephalin within striatal regions. Furthermore, the functional connectivity elicited by food cues, as assessed by an inter-regional multigene-expression correlation method, differed substantially from that elicited by neutral cues. Specifically, food cues increased cortical engagement of the striatum, and within the nucleus accumbens, shifted correlations away from the shell towards the core. Exposure to the food-associated context also induced correlated gene expression between corticostriatal networks and the basolateral amygdala, an area critical for learning and responding to the incentive value of sensory stimuli. This increased corticostriatal-amygdalar functional connectivity was absent in the control group exposed to innocuous cues.</p> <p>Conclusion</p> <p>The results implicate correlated activity between the cortex and the striatum, especially the nucleus accumbens core and the basolateral amygdala, in the generation of a conditioned motivated state that may promote excessive food intake. The upregulation of a number of genes in unique patterns within corticostriatal, thalamic, and hypothalamic networks suggests that food cues are capable of powerfully altering neuronal processing in areas mediating the integration of emotion, cognition, arousal, and the regulation of energy balance. As many of these genes play a role in plasticity, their upregulation within these circuits may also indicate the neuroanatomic and transcriptional correlates of extinction learning.</p

Structural characterization, DNA binding study, antioxidant potential and antitumor activity of diorganotin(IV) complexes against human breast cancer cell line MDA-MB-231

Five new organotin(IV) complexes, Me2SnL (1), n-Bu2SnL (2), tert-Bu2SnL (3), Ph2SnL (4) and n-Oct2SnL (5), have been synthesized from the reaction of R2SnCl2 (R= Me, Bu, tert-Bu, Ph, Oct) with N'-(3-ethoxy-2-hydroxybenzylidene)formohydrazide (H2L). The structural elucidation of synthesized compounds was done by FT-IR, 1H-NMR, 13C-NMR spectroscopy and single-crystal X-ray analysis. Crystallographic data of complex (1) showed seven coordinated central tin atom with distorted pentagonal bipyramidal geometry. Where in solution the Sn atom of synthesized complexes exhibit five coordination, confirmed from 1H-NMR. The results from DNA interaction studies via UV-visible spectroscopy, viscosity, cyclic voltammetry, and differential pulse voltammetry (DPV) suggested an intercalative mode of interaction between the synthesized compounds and SS-DNA. Furthermore, the complexes interact more significantly than ligand. Electrochemical and thermodynamic parameters, including diffusion coefficient, ∆H, ∆G, and ∆S, were calculated using cyclic voltammetry data. The linear plot of peak current (I) vs. square root of the scan rate (υ1/2) indicated the electrochemical processes to be diffusion controlled. The DPPH free radical scavenging assay results showed that complex (4) is an active antioxidant. In-vitro cytotoxicity of the synthesized compounds was determined on human breast cancer cell line MDA-MB-231 using tetrazolium-based MTT assay, and complexes (2), (3) and (4) showed significant cytotoxic activity. The structure-activity relationships may be utilised to direct the optimization of the activity of agents from this class of compounds by comparing the specifics of the compound structures, their DNA binding, and toxicity

Cost Analysis of Medicare Patients with Varying Complexities Who Underwent Total Knee Arthroplasty.

The effort to reduce overall healthcare costs may affect more complex patients, as their pre- and postoperative care can be substantially involved. Therefore, the purpose of this study was to use a large nationwide insurance database to compare (1) costs, (2) reimbursements, and (3) net losses of 90-day episodes of care (EOC) for total knee arthroplasty (TKA) patients according to Elixhauser\u27s comorbidity index (ECI) scores. All TKAs performed between 2005 and 2014 in the Medicare Standard Analytic Files were extracted from the database and stratified based on ECI scores, ranging from 1 to 5. ECI 1 patients served as the control cohort, while ECI 2, 3, 4, and 5 patients were considered study cohorts. Each study cohort and control cohort were matched based on age and sex, resulting in a total of 715,398 patients included for analysis. Total EOC costs, reimbursements, and total net losses (defined as total EOC costs minus total EOC reimbursements) were compared between the cohorts. Overall, total EOC costs increased with ECI. For example, compared with the matched ECI 1 cohorts, the total EOC costs for ECI 5 patients ($56,589.19 vs.$51,747.54) were significantly greater (p \u3c 0.01). Although reimbursements increased with increasing ECI, so did net losses. The net losses for ECI 5 patients were greater than that for ECI 1 patients ($42,309.39 vs.$40,007.82). The bundled payments for care improvement (BPCI) and comprehensive care for joint replacement (CJR) are alternative payment models that might de-incentivize treatment of more complex patients. Our study found that despite increasing reimbursements, overall costs, and therefore net losses, were greater for more complex patients with higher ECI scores