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Jia Cheng, Gali Umschweif, Jenny Leung, Yotam Sagi, Paul Greengard
Cholinergic interneurons (ChIs) in the nucleus accumbens (NAc) have been implicated in drug addiction, reward, and mood disorders. However, the physiological role of ChIs in depression has not been characterized. Here, we show that the tonic firing rate of ChIs in NAc shell is reduced in chronic stress mouse models and in a genetic mouse model of depression. Chemogenetic inhibition of NAc ChIs renders naive mice susceptible to stress, whereas enhancement of ChI activity reverses depressive phenotypes. As a component of the molecular mechanism, we found that the expression and function of the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) are decreased in ChIs of NAc shell in depressed mice...
January 3, 2019: Neuron
Yue Li, Chun-Yue Li, Wang Xi, Sen Jin, Zuo-Hang Wu, Ping Jiang, Ping Dong, Xiao-Bin He, Fu-Qiang Xu, Shumin Duan, Yu-Dong Zhou, Xiao-Ming Li
Both the ventral tegmental area (VTA) and dorsal raphe nucleus (DRN) are involved in affective control and reward-related behaviors. Moreover, the neuronal activities of the VTA and DRN are modulated by opioids. However, the precise circuits from the VTA to DRN and how opioids modulate these circuits remain unknown. Here, we found that neurons projecting from the VTA to DRN are primarily GABAergic. Rostral VTA (rVTA) GABAergic neurons preferentially innervate DRN GABAergic neurons, thus disinhibiting DRN serotonergic neurons...
December 28, 2018: Neuron
Taito Matsuda, Takashi Irie, Shutaro Katsurabayashi, Yoshinori Hayashi, Tatsuya Nagai, Nobuhiko Hamazaki, Aliya Mari D Adefuin, Fumihito Miura, Takashi Ito, Hiroshi Kimura, Katsuhiko Shirahige, Tadayuki Takeda, Katsunori Iwasaki, Takuya Imamura, Kinichi Nakashima
Minimal sets of transcription factors can directly reprogram somatic cells into neurons. However, epigenetic remodeling during neuronal reprogramming has not been well reconciled with transcriptional regulation. Here we show that NeuroD1 achieves direct neuronal conversion from mouse microglia both in vitro and in vivo. Exogenous NeuroD1 initially occupies closed chromatin regions associated with bivalent trimethylation of histone H3 at lysine 4 (H3K4me3) and H3K27me3 marks in microglia to induce neuronal gene expression...
December 28, 2018: Neuron
Yuhki Saito, Yuan Yuan, Ilana Zucker-Scharff, John J Fak, Saša Jereb, Yoko Tajima, Donny D Licatalosi, Robert B Darnell
RNA-binding proteins (RBPs) regulate genetic diversity, but the degree to which they do so in individual cell types in vivo is unknown. We developed NOVA2 cTag-crosslinking and immunoprecipitation (CLIP) to generate functional RBP-RNA maps from different neuronal populations in the mouse brain. Combining cell type datasets from Nova2-cTag and Nova2 conditional knockout mice revealed differential NOVA2 regulatory actions on alternative splicing (AS) on the same transcripts expressed in different neurons. This includes functional differences in transcripts expressed in cortical and cerebellar excitatory versus inhibitory neurons, where we find NOVA2 is required for, respectively, development of laminar structure, motor coordination, and synapse formation...
December 28, 2018: Neuron
Qingyun Li, Zuolin Cheng, Lu Zhou, Spyros Darmanis, Norma F Neff, Jennifer Okamoto, Gunsagar Gulati, Mariko L Bennett, Lu O Sun, Laura E Clarke, Julia Marschallinger, Guoqiang Yu, Stephen R Quake, Tony Wyss-Coray, Ben A Barres
Microglia are increasingly recognized for their major contributions during brain development and neurodegenerative disease. It is currently unknown whether these functions are carried out by subsets of microglia during different stages of development and adulthood or within specific brain regions. Here, we performed deep single-cell RNA sequencing (scRNA-seq) of microglia and related myeloid cells sorted from various regions of embryonic, early postnatal, and adult mouse brains. We found that the majority of adult microglia expressing homeostatic genes are remarkably similar in transcriptomes, regardless of brain region...
December 27, 2018: Neuron
Yuta Senzai, Antonio Fernandez-Ruiz, György Buzsáki
The relationship between mesoscopic local field potentials (LFPs) and single-neuron firing in the multi-layered neocortex is poorly understood. Simultaneous recordings from all layers in the primary visual cortex (V1) of the behaving mouse revealed functionally defined layers in V1. The depth of maximum spike power and sink-source distributions of LFPs provided consistent laminar landmarks across animals. Coherence of gamma oscillations (30-100 Hz) and spike-LFP coupling identified six physiological layers and further sublayers...
December 21, 2018: Neuron
Sarah M Neuner, Sarah E Heuer, Matthew J Huentelman, Kristen M S O'Connell, Catherine C Kaczorowski
An individual's genetic makeup plays a large role in determining susceptibility to Alzheimer's disease (AD) but has largely been ignored in preclinical studies. To test the hypothesis that incorporating genetic diversity into mouse models of AD would improve translational potential, we combined a well-established mouse model of AD with a genetically diverse reference panel to generate mice that harbor identical high-risk human mutations but differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of human AD mutations on both cognitive and pathological phenotypes...
December 21, 2018: Neuron
Ambarish S Pawar, Sergei Gepshtein, Sergey Savel'ev, Thomas D Albright
Cortical sensory neurons are characterized by selectivity to stimulation. This selectivity was originally viewed as a part of the fundamental "receptive field" characteristic of neurons. This view was later challenged by evidence that receptive fields are modulated by stimuli outside of the classical receptive field. Here, we show that even this modified view of selectivity needs revision. We measured spatial frequency selectivity of neurons in cortical area MT of alert monkeys and found that their selectivity strongly depends on luminance contrast, shifting to higher spatial frequencies as contrast increases...
December 20, 2018: Neuron
Stephen R Williams, Lee N Fletcher
The ascending cholinergic system dynamically regulates sensory perception and cognitive function, but it remains unclear how this modulation is executed in neocortical circuits. Here, we demonstrate that the cholinergic system controls the integrative operations of neocortical principal neurons by modulating dendritic excitability. Direct dendritic recordings revealed that the optogenetic-evoked release of acetylcholine (ACh) transformed the pattern of dendritic integration in layer 5B pyramidal neurons, leading to the generation of dendritic plateau potentials which powerfully drove repetitive action potential output...
December 19, 2018: Neuron
Renée S Koolschijn, Uzay E Emir, Alexandros C Pantelides, Hamed Nili, Timothy E J Behrens, Helen C Barron
Our experiences often overlap with each other, yet we are able to selectively recall individual memories to guide decisions and future actions. The neural mechanisms that support such precise memory recall remain unclear. Here, using ultra-high field 7T MRI we reveal two distinct mechanisms that protect memories from interference. The first mechanism involves the hippocampus, where the blood-oxygen-level-dependent (BOLD) signal predicts behavioral measures of memory interference, and representations of context-dependent memories are pattern separated according to their relational overlap...
December 14, 2018: Neuron
Daniel Duran, Xue Zeng, Sheng Chih Jin, Jungmin Choi, Carol Nelson-Williams, Bogdan Yatsula, Jonathan Gaillard, Charuta Gavankar Furey, Qiongshi Lu, Andrew T Timberlake, Weilai Dong, Michelle A Sorscher, Erin Loring, Jennifer Klein, August Allocco, Ava Hunt, Sierra Conine, Jason K Karimy, Mark W Youngblood, Jinwei Zhang, Michael L DiLuna, Charles C Matouk, Shrikant Mane, Irina R Tikhonova, Christopher Castaldi, Francesc López-Giráldez, James Knight, Shozeb Haider, Mariya Soban, Seth L Alper, Masaki Komiyama, Andrew F Ducruet, Joseph M Zabramski, Alan Dardik, Brian P Walcott, Christopher J Stapleton, Beverly Aagaard-Kienitz, Georges Rodesch, Eric Jackson, Edward R Smith, Darren B Orbach, Alejandro Berenstein, Kaya Bilguvar, Miikka Vikkula, Murat Gunel, Richard P Lifton, Kristopher T Kahle
Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development...
December 13, 2018: Neuron
Chengcheng Huang, Douglas A Ruff, Ryan Pyle, Robert Rosenbaum, Marlene R Cohen, Brent Doiron
Trial-to-trial variability is a reflection of the circuitry and cellular physiology that make up a neuronal network. A pervasive yet puzzling feature of cortical circuits is that despite their complex wiring, population-wide shared spiking variability is low dimensional. Previous model cortical networks cannot explain this global variability, and rather assume it is from external sources. We show that if the spatial and temporal scales of inhibitory coupling match known physiology, networks of model spiking neurons internally generate low-dimensional shared variability that captures population activity recorded in vivo...
December 12, 2018: Neuron
Perrine Royal, Alba Andres-Bilbe, Pablo Ávalos Prado, Clément Verkest, Brigitte Wdziekonski, Sébastien Schaub, Anne Baron, Florian Lesage, Xavier Gasull, Joshua Levitz, Guillaume Sandoz
It is often unclear why some genetic mutations to a given gene contribute to neurological disorders and others do not. For instance, two mutations have previously been found to produce a dominant negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2-bp frameshift mutation, and TRESK-C110R. Both mutants inhibit TRESK, but only TRESK-MT increases sensory neuron excitability and is linked to migraine. Here, we identify a new mechanism, termed frameshift mutation-induced alternative translation initiation (fsATI), that may explain why only TRESK-MT is associated with migraine...
December 12, 2018: Neuron
Michele Pignatelli, Tomás J Ryan, Dheeraj S Roy, Chanel Lovett, Lillian M Smith, Shruti Muralidhar, Susumu Tonegawa
Animals need to optimize the efficacy of memory retrieval to adapt to environmental circumstances for survival. The recent development of memory engram labeling technology allows a precise investigation of the processes associated with the recall of a specific memory. Here, we show that engram cell excitability is transiently increased following memory reactivation. This short-term increase of engram excitability enhances the subsequent retrieval of specific memory content in response to cues and is manifest in the animal's ability to recognize contexts more precisely and more effectively...
December 10, 2018: Neuron
Jorge Jaramillo, Jorge F Mejias, Xiao-Jing Wang
Computational modeling of brain mechanisms of cognition has largely focused on the cortex, but recent experiments have shown that higher-order nuclei of the thalamus participate in major cognitive functions and are implicated in psychiatric disorders. Here, we show that a pulvino-cortical circuit model, composed of the pulvinar and two cortical areas, captures several physiological and behavioral observations related to the macaque pulvinar. Effective connections between the two cortical areas are gated by the pulvinar, allowing the pulvinar to shift the operation regime of these areas during attentional processing and working memory and resolve conflict in decision making...
December 6, 2018: Neuron
Matthias Lübbert, R Oliver Goral, Christian Keine, Connon Thomas, Debbie Guerrero-Given, Travis Putzke, Rachel Satterfield, Naomi Kamasawa, Samuel M Young
The abundance of presynaptic CaV 2 voltage-gated Ca2+ channels (CaV 2) at mammalian active zones (AZs) regulates the efficacy of synaptic transmission. It is proposed that presynaptic CaV 2 levels are saturated in AZs due to a finite number of slots that set CaV 2 subtype abundance and that CaV 2.1 cannot compete for CaV 2.2 slots. However, at most AZs, CaV 2.1 levels are highest and CaV 2.2 levels are developmentally reduced. To investigate CaV 2.1 saturation states and preference in AZs, we overexpressed the CaV 2...
December 6, 2018: Neuron
Zheng-Run Gao, Wen-Zhen Chen, Ming-Zhe Liu, Xiao-Jun Chen, Li Wan, Xin-Yan Zhang, Lei Yuan, Jun-Kai Lin, Meng Wang, Li Zhou, Xiao-Hong Xu, Yan-Gang Sun
Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons...
December 5, 2018: Neuron
Nimrod Elazar, Anya Vainshtein, Neev Golan, Bharath Vijayaragavan, Nicole Schaeren-Wiemers, Yael Eshed-Eisenbach, Elior Peles
The initiation of axoglial contact is considered a prerequisite for myelination, yet the role cell adhesion molecules (CAMs) play in mediating such interactions remains unclear. To examine the function of axoglial CAMs, we tested whether enhanced CAM-mediated adhesion between OLs and neurons could affect myelination. Here we show that increased expression of a membrane-bound extracellular domain of Cadm4 (Cadm4dCT) in cultured oligodendrocytes results in the production of numerous axoglial contact sites that fail to elongate and generate mature myelin...
December 5, 2018: Neuron
Johannes Passecker, Nace Mikus, Hugo Malagon-Vina, Philip Anner, Jordane Dimidschstein, Gordon Fishell, Georg Dorffner, Thomas Klausberger
Neuronal signals in the prefrontal cortex have been reported to predict upcoming decisions. Such activity patterns are often coupled to perceptual cues indicating correct choices or values of different options. How does the prefrontal cortex signal future decisions when no cues are present but when decisions are made based on internal valuations of past experiences with stochastic outcomes? We trained rats to perform a two-arm bandit-task, successfully adjusting choices between certain-small or possible-big rewards with changing long-term advantages...
December 5, 2018: Neuron
Martina Sgritta, Sean W Dooling, Shelly A Buffington, Eric N Momin, Michael B Francis, Robert A Britton, Mauro Costa-Mattioli
Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models...
December 3, 2018: Neuron
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