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1.
Sci Adv ; 10(21): eadj8769, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38787942

ABSTRACT

Circular RNAs (circRNAs) are a large class of noncoding RNAs. Despite the identification of thousands of circular transcripts, the biological significance of most of them remains unexplored, partly because of the lack of effective methods for generating loss-of-function animal models. In this study, we focused on circTulp4, an abundant circRNA derived from the Tulp4 gene that is enriched in the brain and synaptic compartments. By creating a circTulp4-deficient mouse model, in which we mutated the splice acceptor site responsible for generating circTulp4 without affecting the linear mRNA or protein levels, we were able to conduct a comprehensive phenotypic analysis. Our results demonstrate that circTulp4 is critical in regulating neuronal and brain physiology, modulating the strength of excitatory neurotransmission and sensitivity to aversive stimuli. This study provides evidence that circRNAs can regulate biologically relevant functions in neurons, with modulatory effects at multiple levels of the phenotype, establishing a proof of principle for the regulatory role of circRNAs in neural processes.


Subject(s)
Brain , RNA, Circular , Synaptic Transmission , RNA, Circular/genetics , Animals , Mice , Brain/metabolism , Brain/physiology , Mice, Knockout , Neurons/metabolism , Neurons/physiology
2.
Neuron ; 111(5): 727-738.e8, 2023 03 01.
Article in English | MEDLINE | ID: mdl-36610397

ABSTRACT

Top-down projections convey a family of signals encoding previous experiences and current aims to the sensory neocortex, where they converge with external bottom-up information to enable perception and memory. Whereas top-down control has been attributed to excitatory pathways, the existence, connectivity, and information content of inhibitory top-down projections remain elusive. Here, we combine synaptic two-photon calcium imaging, circuit mapping, cortex-dependent learning, and chemogenetics in mice to identify GABAergic afferents from the subthalamic zona incerta as a major source of top-down input to the neocortex. Incertocortical transmission undergoes robust plasticity during learning that improves information transfer and mediates behavioral memory. Unlike excitatory pathways, incertocortical afferents form a disinhibitory circuit that encodes learned top-down relevance in a bidirectional manner where the rapid appearance of negative responses serves as the main driver of changes in stimulus representation. Our results therefore reveal the distinctive contribution of long-range (dis)inhibitory afferents to the computational flexibility of neocortical circuits.


Subject(s)
Neocortex , Zona Incerta , Mice , Animals , Neocortex/physiology , Learning/physiology
3.
Trends Neurosci ; 46(1): 20-31, 2023 01.
Article in English | MEDLINE | ID: mdl-36428192

ABSTRACT

Accurate perception of the environment is a constructive process that requires integration of external bottom-up sensory signals with internally generated top-down information. Decades of work have elucidated how sensory neocortex processes physical stimulus features. By contrast, examining how top-down information is encoded and integrated with bottom-up signals has been challenging using traditional neuroscience methods. Recent technological advances in functional imaging of brain-wide afferents in behaving mice have enabled the direct measurement of top-down information. Here, we review the emerging literature on encoding of these internally generated signals by different projection systems enriched in neocortical layer 1 during defined brain functions, including memory, attention, and predictive coding. Moreover, we identify gaps in current knowledge and highlight future directions for this rapidly advancing field.


Subject(s)
Neocortex , Mice , Animals , Attention , Sensation
4.
Science ; 370(6518): 844-848, 2020 11 13.
Article in English | MEDLINE | ID: mdl-33184213

ABSTRACT

The sensory neocortex is a critical substrate for memory. Despite its strong connection with the thalamus, the role of direct thalamocortical communication in memory remains elusive. We performed chronic in vivo two-photon calcium imaging of thalamic synapses in mouse auditory cortex layer 1, a major locus of cortical associations. Combined with optogenetics, viral tracing, whole-cell recording, and computational modeling, we find that the higher-order thalamus is required for associative learning and transmits memory-related information that closely correlates with acquired behavioral relevance. In turn, these signals are tightly and dynamically controlled by local presynaptic inhibition. Our results not only identify the higher-order thalamus as a highly plastic source of cortical top-down information but also reveal a level of computational flexibility in layer 1 that goes far beyond hard-wired connectivity.


Subject(s)
Association Learning/physiology , Auditory Cortex/physiology , Memory/physiology , Thalamus/physiology , Animals , Mice , Mice, Inbred C57BL , Neocortex/physiology , Neural Pathways/physiology , Optogenetics , Patch-Clamp Techniques , Synapses/physiology
5.
Cell Rep ; 28(9): 2264-2274.e3, 2019 08 27.
Article in English | MEDLINE | ID: mdl-31461644

ABSTRACT

Generation of neuronal types at the right time, location, and number is essential for building a functional nervous system. Significant progress has been reached in understanding the mechanisms that govern neuronal diversity. Cerebrospinal fluid-contacting neurons (CSF-cNs), an intriguing spinal cord central canal population, are produced during advanced developmental stages, simultaneous with glial and ependymal cells. It is unknown how CSF-cNs are specified after the neurogenesis-to-gliogenesis switch. Here, we identify delayed Ascl1 expression in mouse spinal progenitors during the gliogenic phase as key in CSF-cN differentiation. With fate mappings and time-controlled deletions, we demonstrate that CSF-cNs derive from Ascl1-expressing cells and that Ascl1 triggers late neurogenesis in the amniote spinal cord. Ascl1 abrogation transforms prospective CSF-cN progenitors into ependymocytes. These results demonstrate that late spinal progenitors have the potential to produce neurons and that Ascl1 initiates CSF-cN differentiation, controlling the precise neuronal and nonneuronal composition of the spinal central canal.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Ependyma/metabolism , Neurogenesis , Neurons/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Ependyma/cytology , Mice , Neurons/cytology , Spinal Cord/cytology , Spinal Cord/embryology , Spinal Cord/metabolism , Zebrafish
6.
Neuron ; 101(6): 994-996, 2019 03 20.
Article in English | MEDLINE | ID: mdl-30897364

ABSTRACT

Memorizing significant locations in the environment is a fundamental capacity of the brain. In this issue, Turi et al. (2019) present multidisciplinary evidence for a critical involvement of disinhibitory interneurons in hippocampal CA1 in this process.


Subject(s)
Spatial Learning , Vasoactive Intestinal Peptide , Goals , Hippocampus , Interneurons
7.
Neuron ; 100(3): 684-699.e6, 2018 11 07.
Article in English | MEDLINE | ID: mdl-30269988

ABSTRACT

A wealth of data has elucidated the mechanisms by which sensory inputs are encoded in the neocortex, but how these processes are regulated by the behavioral relevance of sensory information is less understood. Here, we focus on neocortical layer 1 (L1), a key location for processing of such top-down information. Using Neuron-Derived Neurotrophic Factor (NDNF) as a selective marker of L1 interneurons (INs) and in vivo 2-photon calcium imaging, electrophysiology, viral tracing, optogenetics, and associative memory, we find that L1 NDNF-INs mediate a prolonged form of inhibition in distal pyramidal neuron dendrites that correlates with the strength of the memory trace. Conversely, inhibition from Martinotti cells remains unchanged after conditioning but in turn tightly controls sensory responses in NDNF-INs. These results define a genetically addressable form of dendritic inhibition that is highly experience dependent and indicate that in addition to disinhibition, salient stimuli are encoded at elevated levels of distal dendritic inhibition. VIDEO ABSTRACT.


Subject(s)
Dendrites/physiology , Interneurons/physiology , Learning/physiology , Neuronal Plasticity/physiology , Animals , Dendrites/chemistry , Interneurons/chemistry , Male , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Organ Culture Techniques
8.
Science ; 335(6073): 1238-42, 2012 Mar 09.
Article in English | MEDLINE | ID: mdl-22282476

ABSTRACT

The adult dentate gyrus generates new granule cells (GCs) that develop over several weeks and integrate into the preexisting network. Although adult hippocampal neurogenesis has been implicated in learning and memory, the specific role of new GCs remains unclear. We examined whether immature adult-born neurons contribute to information encoding. By combining calcium imaging and electrophysiology in acute slices, we found that weak afferent activity recruits few mature GCs while activating a substantial proportion of the immature neurons. These different activation thresholds are dictated by an enhanced excitation/inhibition balance transiently expressed in immature GCs. Immature GCs exhibit low input specificity that switches with time toward a highly specific responsiveness. Therefore, activity patterns entering the dentate gyrus can undergo differential decoding by a heterogeneous population of GCs originated at different times.


Subject(s)
Dentate Gyrus/cytology , Dentate Gyrus/physiology , Neural Inhibition , Neurogenesis , Neurons/physiology , Synaptic Potentials , Animals , Electric Stimulation , Entorhinal Cortex/cytology , Entorhinal Cortex/physiology , Excitatory Postsynaptic Potentials , Female , GABAergic Neurons/physiology , Glutamic Acid/metabolism , Inhibitory Postsynaptic Potentials , Mice , Mice, Inbred C57BL , Neuronal Plasticity , Neurons/cytology , Patch-Clamp Techniques , Perforant Pathway , Synapses/physiology
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