| 1. |
- Beets, Isabel, et al.
(författare)
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Natural Variation in a Dendritic Scaffold Protein Remodels Experience-Dependent Plasticity by Altering Neuropeptide Expression
- 2020
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Ingår i: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 105:1, s. 106-121
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Tidskriftsartikel (refereegranskat)abstract
- The extent to which behavior is shaped by experience varies between individuals. Genetic differences contribute to this variation, but the neural mechanisms are not understood. Here, we dissect natural variation in the behavioral flexibility of two Caenorhabditis elegans wild strains. In one strain, a memory of exposure to 21% O2 suppresses CO2-evoked locomotory arousal; in the other, CO2 evokes arousal regardless of previous O2 experience. We map that variation to a polymorphic dendritic scaffold protein, ARCP-1, expressed in sensory neurons. ARCP-1 binds the Ca2+-dependent phosphodiesterase PDE-1 and co-localizes PDE-1 with molecular sensors for CO2 at dendritic ends. Reducing ARCP-1 or PDE-1 activity promotes CO2 escape by altering neuropeptide expression in the BAG CO2 sensors. Variation in ARCP-1 alters behavioral plasticity in multiple paradigms. Our findings are reminiscent of genetic accommodation, an evolutionary process by which phenotypic flexibility in response to environmental variation is reset by genetic change.
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| 2. |
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| 3. |
- Brincat, Scott L., et al.
(författare)
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Interhemispheric transfer of working memories
- 2021
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 109:6, s. 1055-1066
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Tidskriftsartikel (refereegranskat)abstract
- Visual working memory (WM) storage is largely independent between the left and right visual hemifields/cerebral hemispheres, yet somehow WM feels seamless. We studied how WM is integrated across hemifields by recording neural activity bilaterally from lateral prefrontal cortex. An instructed saccade during the WM delay shifted the remembered location from one hemifield to the other. Before the shift, spike rates and oscillatory power showed clear signatures of memory laterality. After the shift, the lateralization inverted, consistent with transfer of the memory trace from one hemisphere to the other. Transferred traces initially used different neural ensembles from feedforward-induced ones, but they converged at the end of the delay. Around the time of transfer, synchrony between the two prefrontal hemispheres peaked in theta and beta frequencies, with a directionality consistent with memory trace transfer. This illustrates how dynamics between the two cortical hemispheres can stitch together WM traces across visual hemifields.
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| 4. |
- Bulovaite, Edita, et al.
(författare)
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A brain atlas of synapse protein lifetime across the mouse lifespan
- 2022
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 110:24, s. 4057-
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Tidskriftsartikel (refereegranskat)abstract
- The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.
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| 5. |
- Cowgill, John, et al.
(författare)
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Structure and dynamics of differential ligand binding in the human ρ-type GABAA receptor
- 2023
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 111:21, s. 5-3450
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Tidskriftsartikel (refereegranskat)abstract
- The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABAARs). Pharmacological properties of ρ-type GABAARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels.
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| 6. |
- Dewan, Ramita, et al.
(författare)
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Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
- 2021
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Ingår i: Neuron. - : Elsevier BV. - 1097-4199 .- 0896-6273. ; 109:3
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Tidskriftsartikel (refereegranskat)abstract
- We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
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| 7. |
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| 8. |
- Gau, Rémi, et al.
(författare)
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Brainhack : Developing a culture of open, inclusive, community-driven neuroscience
- 2021
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Ingår i: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 109:11, s. 1769-1775
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Tidskriftsartikel (refereegranskat)abstract
- Brainhack is an innovative meeting format that promotes scientific collaboration and education in an open, inclusive environment. This NeuroView describes the myriad benefits for participants and the research community and how Brainhacks complement conventional formats to augment scientific progress.
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| 10. |
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