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J Neurosci [journal]
- Thermosensory Signaling by TRPM Is Processed by Brain Serotonergic Neurons to Produce Planarian Thermotaxis. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15701-15714.
For most organisms, sensitive recognition of even slight changes in environmental temperature is essential for adjusting their behavioral strategies to ensure homeostasis and survival. However, much remains to be understood about the molecular and cellular processes that regulate thermosensation and the corresponding behavioral responses. Planarians display clear thermotaxis, although they have a relatively simple brain. Here, we devised a quantitative thermotaxis assay and unraveled a neural pathway involved in planarian thermotaxis by combinatory behavioral assays and RNAi analysis. We found that thermosensory neurons that expressed a planarian Dugesia japonica homolog of the Transient Receptor Potential Melastatin family a (DjTRPMa) gene were required for the thermotaxis. Interestingly, although these thermosensory neurons are distributed throughout their body, planarians with a dysfunctional brain due to regeneration-dependent conditional gene knockdown (Readyknock) of the synaptotagmin gene completely lost their thermotactic behavior. These results suggest that brain function is required as a central processor for the thermosensory response. Therefore, we investigated the type(s) of brain neurons involved in processing the thermal signals by gene knockdown of limiting enzymes for neurotransmitter biosynthesis in the brain. We found that serotonergic neurons with dendrites that were elongated toward DjTRPMa-expressing thermosensory neurons might be required for the processing of signals from thermosensory neurons that results in thermotaxis. These results suggest that serotonergic neurons in the brain may interact with thermosensory neurons activated by TRPM ion channels to produce thermotaxis in planarians.
- Swelling and Eicosanoid Metabolites Differentially Gate TRPV4 Channels in Retinal Neurons and Glia. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15689-15700.
Activity-dependent shifts in ionic concentrations and water that accompany neuronal and glial activity can generate osmotic forces with biological consequences for brain physiology. Active regulation of osmotic gradients and cellular volume requires volume-sensitive ion channels. In the vertebrate retina, critical support to volume regulation is provided by Müller astroglia, but the identity of their osmosensor is unknown. Here, we identify TRPV4 channels as transducers of mouse Müller cell volume increases into physiological responses. Hypotonic stimuli induced sustained [Ca(2+)]i elevations that were inhibited by TRPV4 antagonists and absent in TRPV4(-/-) Müller cells. Glial TRPV4 signals were phospholipase A2- and cytochrome P450-dependent, characterized by slow-onset and Ca(2+) waves, and, in excess, were sufficient to induce reactive gliosis. In contrast, neurons responded to TRPV4 agonists and swelling with fast, inactivating Ca(2+) signals that were independent of phospholipase A2. Our results support a model whereby swelling and proinflammatory signals associated with arachidonic acid metabolites differentially gate TRPV4 in retinal neurons and glia, with potentially significant consequences for normal and pathological retinal function.
- Gap Junctions in the Ventral Hippocampal-Medial Prefrontal Pathway Are Involved in Anxiety Regulation. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15679-15688.
Anxiety disorders are highly prevalent but little is known about their underlying mechanisms. Gap junctions exist in brain regions important for anxiety regulation, such as the ventral hippocampus (vHIP) and mPFC, but their functions in these areas have not been investigated. Using pharmacological blockade of neuronal gap junctions combined with electrophysiological recordings, we found that gap junctions play a role in theta rhythm in the vHIP and mPFC of adult mice. Bilateral infusion of neuronal gap junction blockers into the vHIP decreased anxiety-like behavior on the elevated plus maze and open field. Similar anxiolytic effects were observed with unilateral infusion of these drugs into the vHIP combined with contralateral infusion into the mPFC. No change in anxious behavior was observed with gap junction blockade in the unilateral vHIP alone or in the bilateral dorsal HIP. Since physical exercise is known to reduce anxiety, we examined the effects of long-term running on the expression of the neuronal gap junction protein connexin-36 among inhibitory interneurons and found a reduction in the vHIP. Despite this change, we observed no alteration in theta frequency or power in long-term runners. Collectively, these findings suggest that neuronal gap junctions in the vHIP-mPFC pathway are important for theta rhythm and anxiety regulation under sedentary conditions but that additional mechanisms are likely involved in running-induced reduction in anxiety.
- In Vivo Identification of Eugenol-Responsive and Muscone-Responsive Mouse Odorant Receptors. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15669-15678.
Our understanding of mammalian olfactory coding has been impeded by the paucity of information about the odorant receptors (ORs) that respond to a given odorant ligand in awake, freely behaving animals. Identifying the ORs that respond in vivo to a given odorant ligand from among the ∼1100 ORs in mice is intrinsically challenging but critical for our understanding of olfactory coding at the periphery. Here, we report an in vivo assay that is based on a novel gene-targeted mouse strain, S100a5-tauGFP, in which a fluorescent reporter selectively marks olfactory sensory neurons that have been activated recently in vivo. Because each olfactory sensory neuron expresses a single OR gene, multiple ORs responding to a given odorant ligand can be identified simultaneously by capturing the population of activated olfactory sensory neurons and using expression profiling methods to screen the repertoire of mouse OR genes. We used this in vivo assay to re-identify known eugenol- and muscone-responsive mouse ORs. We identified additional ORs responsive to eugenol or muscone. Heterologous expression assays confirmed nine eugenol-responsive ORs (Olfr73, Olfr178, Olfr432, Olfr610, Olfr958, Olfr960, Olfr961, Olfr913, and Olfr1234) and four muscone-responsive ORs (Olfr74, Olfr235, Olfr816, and Olfr1440). We found that the human ortholog of Olfr235 and Olfr1440 responds to macrocyclic ketone and lactone musk odorants but not to polycyclic musk odorants or a macrocyclic diester musk odorant. This novel assay, called the Kentucky in vivo odorant ligand-receptor assay, should facilitate the in vivo identification of mouse ORs for a given odorant ligand of interest.
- Differential Effects of Delayed Aging on Phenotype and Striatal Pathology in a Murine Model of Huntington Disease. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15658-15668.
The common neurodegenerative syndromes exhibit age-related incidence, and many Mendelian neurodegenerative diseases exhibit age-related penetrance. Mutations slowing aging retard age related pathologies. To assess whether delayed aging retards the effects of a mutant allele causing a Huntington's disease (HD)-like syndrome, we generated compound mutant mice, placing a dominant HD knock-in polyglutamine allele onto the slow-aging Snell dwarf genotype. The Snell genotype did not affect mutant huntingtin protein expression. Bigenic and control mice were evaluated prospectively from 10 to 100 weeks of age. Adult HD knock-in allele mice lost weight progressively with weight loss blunted significantly in male bigenic HD knock-in/Snell dwarf mice. Impaired balance beam performance developed significantly more slowly in bigenic HD knock-in/Snell dwarf mice. Striatal dopamine receptor expression was diminished significantly and similarly in all HD-like mice, regardless of the Snell genotype. Striatal neuronal intranuclear inclusion burden was similar between HD knock-in mice with and without the Snell genotype, whereas nigral neuropil aggregates were diminished in bigenic HD knock-in/Snell dwarf mice. Compared with control mice, Snell dwarf mice exhibited differences in regional benzodiazepine and cannabinoid receptor binding site expression. These results indicate that delaying aging delayed behavioral decline with little effect on the development of striatal pathology in this model of HD but may have altered synaptic pathology. These results indicate that mutations prolonging lifespan in mice delay onset of significant phenotypic features of this model and also demonstrate dissociation between striatal pathology and a commonly used behavioral measure of disease burden in HD models.
- Functional Compensation in the Ventromedial Prefrontal Cortex Improves Memory-Dependent Decisions in Older Adults. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15648-15657.
Everyday consumer choices frequently involve memory, as when we retrieve information about consumer products when making purchasing decisions. In this context, poor memory may affect decision quality, particularly in individuals with memory decline, such as older adults. However, age differences in choice behavior may be reduced if older adults can recruit additional neural resources that support task performance. Although such functional compensation is well documented in other cognitive domains, it is presently unclear whether it can support memory-guided decision making and, if so, which brain regions play a role in compensation. The current study engaged younger and older humans in a memory-dependent choice task in which pairs of consumer products from a popular online-shopping site were evaluated with different delays between the first and second product. Using functional imaging (fMRI), we found that the ventromedial prefrontal cortex (vmPFC) supports compensation as defined by three a priori criteria: (1) increased vmPFC activation was observed in older versus younger adults; (2) age-related increases in vmPFC activity were associated with increased retrieval demands; and (3) increased vmPFC activity was positively associated with performance in older adults-evidence of successful compensation. Extending these results, we observed evidence for compensation in connectivity between vmPFC and the dorsolateral PFC during memory-dependent choice. In contrast, we found no evidence for age differences in value-related processing or age-related compensation for choices without delayed retrieval. Together, these results converge on the conclusion that age-related decline in memory-dependent choice performance can be minimized via functional compensation in vmPFC.
- Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and cAMP-Dependent Modulation of Exocytosis in Cultured Rat Lactotrophs. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15638-15647.
Hormone and neurotransmitter release from vesicles is mediated by regulated exocytosis, where an aqueous channel-like structure, termed a fusion pore, is formed. It was recently shown that second messenger cAMP modulates the fusion pore, but the detailed mechanisms remain elusive. In this study, we asked whether the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are activated by cAMP, are involved in the regulation of unitary exocytic events. By using the Western blot technique, a real-time PCR, immunocytochemistry in combination with confocal microscopy, and voltage-clamp measurements of hyperpolarizing currents, we show that HCN channels are present in the plasma membrane and in the membrane of secretory vesicles of isolated rat lactotrophs. Single vesicle membrane capacitance measurements of lactotrophs, where HCN channels were either augmented by transfection or blocked with an HCN channel blocker (ZD7288), show modulated fusion pore properties. We suggest that the changes in local cation concentration, mediated through HCN channels, which are located on or near secretory vesicles, have an important role in modulating exocytosis.
- Regulation of Experience-Dependent Bidirectional Chemotaxis by a Neural Circuit Switch in Caenorhabditis elegans. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15631-15637.
The nematode Caenorhabditis elegans changes its chemotaxis to NaCl depending on previous experience. At the behavioral level, this chemotactic plasticity is generated by reversing the elementary behaviors for chemotaxis, klinotaxis, and klinokinesis. Here, we report that bidirectional klinotaxis is achieved by the proper use of at least two different neural subcircuits. We simulated an NaCl concentration change by activating an NaCl-sensitive chemosensory neuron in phase with head swing and successfully induced klinotaxis-like curving. The curving direction reversed depending on preconditioning, which was consistent with klinotaxis plasticity under a real concentration gradient. Cell-specific ablation and activation of downstream interneurons revealed that ASER-evoked curving toward lower concentration was mediated by AIY interneurons, whereas curving to the opposite direction was not. These results suggest that the experience-dependent bidirectionality of klinotaxis is generated by a switch between different neural subcircuits downstream of the chemosensory neuron.
- Learning To Minimize Efforts versus Maximizing Rewards: Computational Principles and Neural Correlates. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15621-15630.
The mechanisms of reward maximization have been extensively studied at both the computational and neural levels. By contrast, little is known about how the brain learns to choose the options that minimize action cost. In principle, the brain could have evolved a general mechanism that applies the same learning rule to the different dimensions of choice options. To test this hypothesis, we scanned healthy human volunteers while they performed a probabilistic instrumental learning task that varied in both the physical effort and the monetary outcome associated with choice options. Behavioral data showed that the same computational rule, using prediction errors to update expectations, could account for both reward maximization and effort minimization. However, these learning-related variables were encoded in partially dissociable brain areas. In line with previous findings, the ventromedial prefrontal cortex was found to positively represent expected and actual rewards, regardless of effort. A separate network, encompassing the anterior insula, the dorsal anterior cingulate, and the posterior parietal cortex, correlated positively with expected and actual efforts. These findings suggest that the same computational rule is applied by distinct brain systems, depending on the choice dimension-cost or benefit-that has to be learned.
- Reward Activates Stimulus-Specific and Task-Dependent Representations in Visual Association Cortices. [JOURNAL ARTICLE]
- J Neurosci 2014 Nov 19; 34(47):15610-15620.
Humans reliably learn which actions lead to rewards. One prominent question is how credit is assigned to environmental stimuli that are acted upon. Recent functional magnetic resonance imaging (fMRI) studies have provided evidence that representations of rewarded stimuli are activated upon reward delivery, providing possible eligibility traces for credit assignment. Our study sought evidence of postreward activation in sensory cortices satisfying two conditions of instrumental learning: postreward activity should reflect the stimulus category that preceded reward (stimulus specificity), and should occur only if the stimulus was acted on to obtain reward (task dependency). Our experiment implemented two tasks in the fMRI scanner. The first was a perceptual decision-making task on degraded face and house stimuli. Stimulus specificity was evident as rewards activated the sensory cortices associated with face versus house perception more strongly after face versus house decisions, respectively, particularly in the fusiform face area. Stimulus specificity was further evident in a psychophysiological interaction analysis wherein face-sensitive areas correlated with nucleus accumbens activity after face-decision rewards, whereas house-sensitive areas correlated with nucleus accumbens activity after house-decision rewards. The second task required participants to make an instructed response. The criterion of task dependency was fulfilled as rewards after face versus house responses activated the respective association cortices to a larger degree when faces and houses were relevant to the performed task. Our study is the first to show that postreward sensory cortex activity meets these two key criteria of credit assignment, and does so independently from bottom-up perceptual processing.