In order to localize the neural circuits involved in generating behaviors, it is necessary to assign activity onto anatomical maps of the nervous system. Using brain registration across hundreds of ...larval zebrafish, we have built an expandable open-source atlas containing molecular labels and definitions of anatomical regions, the Z-Brain. Using this platform and immunohistochemical detection of phosphorylated extracellular signal–regulated kinase (ERK) as a readout of neural activity, we have developed a system to create and contextualize whole-brain maps of stimulus- and behavior-dependent neural activity. This mitogen-activated protein kinase (MAP)-mapping assay is technically simple, and data analysis is completely automated. Because MAP-mapping is performed on freely swimming fish, it is applicable to studies of nearly any stimulus or behavior. Here we demonstrate our high-throughput approach using pharmacological, visual and noxious stimuli, as well as hunting and feeding. The resultant maps outline hundreds of areas associated with behaviors.
Animal brains have evolved to encode social stimuli and transform these representations into advantageous behavioral responses. The commonalities and differences of these representations across ...species are not well-understood. Here, we show that social isolation activates an oxytocinergic (OXT), nociceptive circuit in the larval zebrafish hypothalamus and that chemical cues released from conspecific animals are potent modulators of this circuit's activity. We delineate an olfactory to subpallial pathway that transmits chemical social cues to OXT circuitry, where they are transformed into diverse outputs simultaneously regulating avoidance and feeding behaviors. Our data allow us to propose a model through which social stimuli are integrated within a fundamental neural circuit to mediate diverse adaptive behaviours.
The Mauthner cell (M-cell) is a command-like neuron in teleost fish whose firing in response to aversive stimuli is correlated with short-latency escapes 1–3. M-cells have been proposed as ...evolutionary ancestors of startle response neurons of the mammalian reticular formation 4, and studies of this circuit have uncovered important principles in neurobiology that generalize to more complex vertebrate models 3. The main excitatory input was thought to originate from multisensory afferents synapsing directly onto the M-cell dendrites 3. Here, we describe an additional, convergent pathway that is essential for the M-cell-mediated startle behavior in larval zebrafish. It is composed of excitatory interneurons called spiral fiber neurons, which project to the M-cell axon hillock. By in vivo calcium imaging, we found that spiral fiber neurons are active in response to aversive stimuli capable of eliciting escapes. Like M-cell ablations, bilateral ablations of spiral fiber neurons largely eliminate short-latency escapes. Unilateral spiral fiber neuron ablations shift the directionality of escapes and indicate that spiral fiber neurons excite the M-cell in a lateralized manner. Their optogenetic activation increases the probability of short-latency escapes, supporting the notion that spiral fiber neurons help activate M-cell-mediated startle behavior. These results reveal that spiral fiber neurons are essential for the function of the M-cell in response to sensory cues and suggest that convergent excitatory inputs that differ in their input location and timing ensure reliable activation of the M-cell, a feedforward excitatory motif that may extend to other neural circuits.
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•Spiral fiber neurons excite Mauthner cells, which mediate fast escape behavior•Calcium imaging reveals that spiral fiber neurons encode aversive sensory cues•Ablation and optogenetic experiments indicate that they are essential for escapes•This study uncovers the crucial role of a feedforward excitatory motif for behavior
Lacoste et al. find that excitatory interneurons form an essential feedforward pathway for the Mauthner-cell-mediated startle behavior of larval zebrafish. Together with direct sensory afferents on the lateral dendrites, the input of spiral fiber neurons at the axon hillock of the Mauthner cell enables fast escapes in response to noxious stimuli.
Animals have evolved specialized neural circuits to defend themselves from pain- and injury-causing stimuli. Using a combination of optical, behavioral and genetic approaches in the larval zebrafish, ...we describe a novel role for hypothalamic oxytocin (OXT) neurons in the processing of noxious stimuli. In vivo imaging revealed that a large and distributed fraction of zebrafish OXT neurons respond strongly to noxious inputs, including the activation of damage-sensing TRPA1 receptors. OXT population activity reflects the sensorimotor transformation of the noxious stimulus, with some neurons encoding sensory information and others correlating more strongly with large-angle swims. Notably, OXT neuron activation is sufficient to generate this defensive behavior via the recruitment of brainstem premotor targets, whereas ablation of OXT neurons or loss of the peptide attenuates behavioral responses to TRPA1 activation. These data highlight a crucial role for OXT neurons in the generation of appropriate defensive responses to noxious input.
Drug response variations amongst different individuals/populations are influenced by several factors including allele frequency differences of single nucleotide polymorphisms (SNPs) that functionally ...affect drug-response genes. Here, we aim to identify drugs that potentially exhibit population differences in response using SNP data mining and analytics. Ninety-one pairwise-comparisons of >22,000,000 SNPs from the 1000 Genomes Project, across 14 different populations, were performed to identify 'population-differentiated' SNPs (pdSNPs). Potentially-functional pdSNPs (pf-pdSNPs) were then selected, mapped into genes, and integrated with drug-gene databases to identify 'population-differentiated' drugs enriched with genes carrying pf-pdSNPs. 1191 clinically-approved drugs were found to be significantly enriched (Z > 2.58) with genes carrying SNPs that were differentiated in one or more population-pair comparisons. Thirteen drugs were found to be enriched with such differentiated genes across all 91 population-pairs. Notably, 82% of drugs, which were previously reported in the literature to exhibit population differences in response were also found by this method to contain a significant enrichment of population specific differentiated SNPs. Furthermore, drugs with genetic testing labels, or those suspected to cause adverse reactions, contained a significantly larger number (P < 0.01) of population-pairs with enriched pf-pdSNPs compared with those without these labels. This pioneering effort at harnessing big-data pharmacogenomics to identify 'population differentiated' drugs could help to facilitate data-driven decision-making for a more personalized medicine.
Population variation in disease and other phenotype are partly attributed to single nucleotide polymorphisms (SNPs) in the human genome. Due to selection pressure, two individuals from the same ...ancestral population have more genetic similarity compared to individuals from further geographic regions. Here, we elucidated the genomic population differentiation pattern, by interrogating >22,000,000 SNPs. Majority of population-differentiated (pd) SNPs (~95%), including the potentially functional (pf) (~84%) subset reside in non-genic regions, compared to the proportion of all SNPs (58%) found in non-genic regions. This suggests that differences between populations are more likely due to differences in gene regulation rather than protein function. Actin Cytoskeleton, Axonal Guidance and Protein Kinase A signaling pathways are enriched with genes carrying at least three pdSNPs (enriched pdGenes), while Antigen Presentation, Hepatic Fibrosis and Huntington Disease Signalling pathways are over-represented by enriched pf-pdGenes. An inverse correlation between chromosome size and the proportion of pd-/pf-pdSNPs was observed. Smaller chromosomes have relatively more of such SNPs including genes carrying these SNPs. Genes associated with common diseases and enriched with these pd-/pfpdSNPs are localized to 11 different chromosomes, with immune-related disease pd/pf-pdGenes mainly residing in chromosome 6 while neurological disease pd/pf-pdGenes residing in smaller chromosomes including chromosome 21/22. The associated diseases were reported to show population differences in incidence, severity and/or etiology. In summary, this study highlights the non-sporadic nature of population differentiation footprint in the human genome, which can potentially lead to the identification of genomic regions that play roles in the manifestation of phenotypic differences, including in disease predisposition and drug response.
Arc is an immediate-early gene whose genetic ablation selectively abrogates long-term memory, indicating a critical role in memory consolidation. Although Arc protein is found at synapses, it also ...localizes to the neuronal nucleus, where its function is less understood. Nuclear Arc forms a complex with the β-spectrin isoform βSpIVΣ5 and associates with PML bodies, sites of epigenetic regulation of gene expression. We report here a novel interaction between Arc and Tip60, a histone-acetyltransferase and subunit of a chromatin-remodelling complex, using biochemistry and super-resolution microscopy in primary rat hippocampal neurons. Arc and βSpIVΣ5 are recruited to nuclear Tip60 speckles, and the three proteins form a tight complex that localizes to nuclear perichromatin regions, sites of transcriptional activity. Neuronal activity-induced expression of Arc (1) increases endogenous nuclear Tip60 puncta, (2) recruits Tip60 to PML bodies, and (3) increases histone acetylation of Tip60 substrate H4K12, a learning-induced chromatin modification. These mechanisms point to an epigenetic role for Arc in regulating memory consolidation.
This manuscript reports a novel epigenetic role for the neuronal immediate early gene Arc, a master regulator of synaptic plasticity and critical effector of memory consolidation. Arc protein is ...localized both to synapses, where its role is well studied, and to the nucleus, where its function is still obscure.
Arc is an immediate-early gene whose genetic ablation selectively abrogates long-term memory, indicating a critical role in memory consolidation. Although Arc protein is found at synapses, it also localizes to the neuronal nucleus, where its function is less understood. Nuclear Arc forms a complex with the β-spectrin isoform βSpIVΣ5 and associates with PML bodies, sites of epigenetic regulation of gene expression. We report here a novel interaction between Arc and Tip60, a histone-acetyltransferase and subunit of a chromatin-remodelling complex, using biochemistry and super-resolution microscopy in primary rat hippocampal neurons. Arc and βSpIVΣ5 are recruited to nuclear Tip60 speckles, and the three proteins form a tight complex that localizes to nuclear perichromatin regions, sites of transcriptional activity. Neuronal activity-induced expression of Arc (1) increases endogenous nuclear Tip60 puncta, (2) recruits Tip60 to PML bodies, and (3) increases histone acetylation of Tip60 substrate H4K12, a learning-induced chromatin modification. These mechanisms point to an epigenetic role for Arc in regulating memory consolidation.
High-risk alcohol use after weight loss surgery Wee, Christina C; Mukamal, Kenneth J; Huskey, Karen W ...
Surgery for obesity and related diseases,
05/2014, Letnik:
10, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Bariatric or weight loss surgery (WLS) may alter alcohol metabolism resulting in a higher prevalence of problem drinking postoperatively. Few studies distinguish those who report improvements in ...drinking from those who report worsening behavior after surgery. The objective of this study was to characterize high-risk alcohol use before and after WLS and according to surgery type.
We interviewed patients before and annually after WLS. High-risk alcohol use as assessed via a modified version of the Alcohol Use Disorders Identification Test-Consumption.
Of 541 participants who underwent WLS, 375 (69% retention) completed the 1-year interview and 328 (63% retention) completed the 2-year interview. At 1 year, 13% reported high-risk drinking compared to 17% at baseline, P = .10; at year 2, 13% reported high-risk drinking compared to 15% at baseline, P = .39; 7% and 6% of patients, respectively, reported new high-risk drinking at 1- and 2-year follow-up. At both follow-up time points, more than half of those who reported high-risk drinking at baseline no longer did so. A larger proportion of gastric bypass patients (71%) reported amelioration in high-risk drinking than gastric banding (48%) at year 1, but this difference did not reach statistical significance (P = .07); the difference largely dissipated by year 2 (50% versus 57%) .
Although 7% of patients report new high-risk alcohol use 1 year after WLS, more than half who reported high-risk alcohol use before surgery discontinued high-risk drinking.
Visible-light-driven water splitting was investigated in a dye sensitized photoelectrosynthesis cell (DSPEC) based on a photoanode with a phosphonic acid-derivatized donor−π–acceptor (D−π–A) organic ...chromophore, 1, and the water oxidation catalyst Ru(bda)(4-O(CH2)3P(O3H2)2-pyr)2, 2, (pyr = pyridine; bda = 2,2′-bipyridine-6,6′-dicarboxylate). The photoanode was prepared by using a layering strategy beginning with the organic dye anchored to an FTO|core/shell electrode, atomic layer deposition (ALD) of a thin layer (<1 nm) of TiO2, and catalyst binding through phosphonate linkage to the TiO2 layer. Device performance was evaluated by photocurrent measurements for core/shell photoanodes, with either SnO2 or nanoITO core materials, in acetate-buffered, aqueous solutions at pH 4.6 or 5.7. The absolute magnitudes of photocurrent changes with the core material, TiO2 spacer layer thickness, or pH, observed photocurrents were 2.5-fold higher in the presence of catalyst. The results of transient absorption measurements and DFT calculations show that electron injection by the photoexcited organic dye is ultrafast promoted by electronic interactions enabled by orientation of the dye’s molecular orbitals on the electrode surface. Rapid injection is followed by recombination with the oxidized dye which is 95% complete by 1.5 ns. Although chromophore decomposition limits the efficiency of the DSPEC devices toward O2 production, the flexibility of the strategy presented here offers a new approach to photoanode design.
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